DIPHENYLIMIDAZOLYL COMPOUNDS AS INHIBITORS OF beta-SECRETASE

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient.

BACKGROUND OF THE INVENTION

This application is a divisional of U.S. application Ser. No.11/152,925,filed Jun. 15, 2005, which claims the benefit under 35 U.S.C. §119(e) toU.S. provisional application no. 60/580187, filed Jun. 16, 2004, both ofwhich are hereby incorporated by reference in their entirety.

Alzheimer's disease (AD), a progressive degenerative disease of thebrain primarily associated with aging, is a serious healthcare problem.Clinically, AD is characterized by the of loss of memory, cognition,reasoning, judgment, and orientation. Also affected, as the diseaseprogresses, are motor, sensory, and linguistic abilities until globalimpairment of multiple cognitive functions occurs. These cognitivelosses take place gradually, but typically lead to severe impairment andeventual death in 4-12 years. Patients with AD display characteristicβ-amyloid deposits in the brain and in cerebral blood vessels (β-amyloidangiopathy) as well as neurofibrillary tangles. Amyloidogenic plaquesand vascular amyloid angiopathy also characterize the brains of patientswith Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerativedisorders. Neurofibrillary tangles also occur in other dementia-inducingdisorders.

The family of proteins known as β-amyloid are thought to be causal forthe pathology and subsequent cognitive decline in Alzheimer's disease.Proteolytic processing of the amyloid precursor protein (APP) generatesamyloid β (A-beta) peptide; specifically, A-beta is produced by thecleavage of APP at the N-terminus by β-secretase and at the C-terminusby one or more γ-secretases. Aspartyl protease enzyme, or β-secretaseenzyme (BACE), activity is correlated directly to the generation ofA-beta peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540).Increasingly, studies indicate that the inhibition of the β-secretaseenzyme, inhibits the production of A-beta peptide. The inhibition ofβ-secretase and consequent lowering of A-beta peptide may lead to thereduction of β-amyloid deposits in the brain and β-amyloid levels in thecerebral blood vessels and to an effective treatment of a disease ordisorder caused thereby.

Therefore, it is an object of this invention to provide compounds whichare inhibitors of β-secretase and are useful as therapeutic agents inthe treatment, prevention or amelioration of a disease or disordercharacterized by elevated β-amyloid deposits or β-amyloid levels in apatient.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient.

It is a feature of this invention that the compounds provided may alsobe useful to further study and elucidate the β-secretase enzyme.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a diphenylimidazopyrimidine or -imidazoleamine of formula I

wherein X is N, NO or CR₁₉;

-   -   Y is N, NO or CR₁₁;    -   Z is N, NO or CR₂₀ with the proviso that no more than two of X,        Y or Z may be N or NO;    -   R₁ and R₂ are each independently H, CN or an optionally        substituted C₁-C₄alkyl group;    -   R₃ and R₄ are each independently H, or an optionally substituted        C₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a        3- to 7-membered ring optionally containing one or two        heteroatoms selected from O, N or S or R₃ may be taken together        with the atom to which it is attached and an adjacent carbon        atom to form a double bond;    -   R₅ and R₆ are each independently H, halogen, NO₂, CN, OR₁₃,        NR₁₄R₁₅ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl or C₃-C₈ cycloalkyl group each optionally 20 substituted        or when attached to adjacent carbon atoms R₅ and R₆ may be taken        together with the atoms to which they are attached to form an        optionally substituted 5- to 7-membered ring optionally        containing one or two heteroatoms selected from O, N or S;    -   R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H,        halogen, NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl        group each optionally substituted;    -   m is 0 or 1;    -   n is 0, 1, 2 or 3;    -   is a single bond or a double bond with the proviso that when m        is 0 then        must be a single bond;    -   R₁₂, R₁₃ and R₁₆ are each independently H or a C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl        or aryl group each optionally substituted; and

R₁₄, R₁₅, R₁₇ and R₁₈ are each independently H or C₁-C₄ alkyl; or atautomer thereof, a stereoisomer thereof or a pharmaceuticallyacceptable salt thereof.

The present invention also provides therapeutic methods andpharmaceutical compositions useful for the treatment, prevention oramelioration of a disease or disorder characterized by increasedβ-amyloid deposits or increased β-amyloid levels in a patient.

DETAILED DESCRIPTION OF THE INVENTION

Alzheimer's disease (AD) is a major degenerative disease of the brainwhich presents clinically by progressive loss of memory, cognition,reasoning, judgement and emotional stability and gradually leads toprofound mental deteoriation and death. The exact cause of AD isunknown, but increasing evidence indicates that amyloid beta peptide(A-beta) plays a central role in the pathogenesis of the disease. (D. B.Schenk; R. E. Rydel et al, Journal of Medicinal Chemistry, 1995, 21,4141 and D. J. Selkoe, Physiology Review, 2001, 81, 741). Patients withAD exhibit characteristic neuropathological markers such as neuriticplaques (and in β-amyloid angiopathy, deposits in cerebral bloodvessels) as well as neurofibrillary tangles detected in the brain atautopsy. A-beta is a major component of neuritic plaques in AD brains.In addition, β-amyloid deposits and vascular β-amyloid angiopathy alsocharacterize individuals with Downs Syndrome, Hereditary CerebralHemmorhage with Amyloidosis of the Dutch type and otherneurodegenreative and dementia-inducing disorders. Over expression ofthe amyloid precursor protein (APP), altered cleavage of APP to A-betaor a decrease in the clearance of A-beta from a patient's brain mayincrease the levels of soluble or fibrullar forms of A-beta in thebrain. The β-site APP cleaving enzyme, BACE1, also called memapsin-2 orAsp-2, was identified in 1999 (R. Vassar, B. D. Bennett, et al, Nature,1999, 402, 537). BACE1 is a membrane-bound aspartic protease with allthe known functional properties and characteristics of β-secretase.Parallel to BACE1, a second homologous aspartyl protease named BACE2 wasfound to have β-secretase activity in vitro. Low molecular weight,non-peptide, non-substrate-related inhibitors of BACE1 or β-secretaseare earnestly sought both as an aid in the study of the β-secretaseenzyme and as potential therapeutic agents.

Surprisingly, it has now been found that diphenylimidazopyrimidine amineor diphenylimidazoimidazole amine compounds of formula I demonstrateinhibition of β-secretase and the selective inhibition of BACE1.Advantageously, said pyrimidinamine or imidazolamine compounds may beused as effective therapeutic agents for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient. Accordingly, thepresent invention provides an imidazopyrimidine or imidazoimidazoleamine compound of formula I

wherein X is N, NO or CR₁₉;

-   -   Y is N, NO or CR₁₁;    -   Z is N, NO or CR₂₀ with the proviso that no more than two of X,        Y or Z may be N or NO;    -   R₁ and R₂ are each independently H, CN or an optionally        substituted C₁-C₄ alkyl group;    -   R₃ and R₄ are each independently H, or an optionally substituted        C₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a        3- to 7-membered ring optionally containing one or two        heteroatoms selected from O, N or S or R₃ may be taken together        with the atom to which it is attached and an adjacent carbon        atom to form a double bond;    -   R₅ and R₆ are each independently H, halogen, NO₂, CN, OR₁₃,        NR₁₄R₁₅ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl or C₃-C₈ cycloalkyl group each optionally substituted or        when attached to adjacent carbon atoms R₅ and R₆ may be taken        together with the atoms to which they are attached to form an        optionally substituted 5- to 7-membered ring optionally        containing one or two heteroatoms selected from O, N or S;    -   R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H,        halogen, NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C3-C₈ cycloalkyl        group each optionally substituted;    -   m is 0 or 1;    -   n is 0, 1, 2 or 3;    -   is a single bond or a double bond with the proviso that when m        is 0 then        must be a single bonds    -   R₁₂, R₁₃ and R₁₆ are each independently H or a C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl        or aryl group each optionally substituted; and

R₁₄, R₁₅, R₁₇ and R₁₈ are each independently H or C₁-C₄ alkyl; or atautomer thereof, a stereoisomer thereof or a pharmaceuticallyacceptable salt thereof.

As used in the specification and claims, the term halogen designates F,Cl, Br or I and the term cycloheteroalkyl designates a five- toseven-membered cycloalkyl ring system containing 1 or 2 heteroatoms,which may be the same or different, selected from N, O or S andoptionally containing one double bond. Exemplary of the cycloheteroalkylring systems included in the term as designated herein are the followingrings wherein X₁ is NR, O or S; and R is H or an optional substituent asdescribed hereinbelow:

Similarly, as used in the specification and claims, the term heteroaryldesignates a five- to ten-membered aromatic ring system containing 1, 2or 3 heteroatoms, which may be the same or different, selected from N, Oor S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm aryl designates a carbocyclic aromatic ring system such as phenyl,naphthyl, anthracenyl or the like. The term aryl(C₁-C₄)alkyl designatesan aryl group as defined hereinabove attached to a C₁-C₄alkyl groupwhich may be straight or branched. Said aryl(C₁-C₄)alkyl groups includebenzyl, phenethyl, napthtylmethyl, or the like. The term haloalkyl asused herein designates a C_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different and the term haloalkoxyas used herein designates an OC_(n)H_(2n+1) group having from one to2n+1 halogen atoms which may be the same or different. Preferably theterm haloalkyl designates CF₃ and the term haloalkoxy designates OCF₃.

In the specification and claims, when the terms C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, cycloheteroalkyl, aryl,aryl(C₁-C₄)alkyl or heteroaryl are designated as being optionallysubstituted, the substituent groups which are optionally present may beone or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl or lower alkoxy groups. Typically, 0-3 substituents maybe present. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

Compounds of the invention may exist as one or more tautomers. Oneskilled in the art will recognize that compounds of formula I may alsoexist as the tautomer It as shown below.

Tautomers often exist in equilibrium with each other. As these tautomersinterconvert under environmental and physiological conditions, theyprovide the same useful biological effects. The present inventionincludes mixtures of such tautomers as well as the individual tautomersof Formula I and Formula It.

The compounds of the invention may contain one or more asymmetric carbonatoms or one or more asymmetric (chiral) centers and may thus give riseto optical isomers and diastereomers. Thus, the invention includes suchoptical isomers and disastereomers; as well as the racemic and resolved,enantiomerically pure stereoisomers; as well as other mixtures of the Rand S stereoisomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of Formula I, thestereoisomers thereof, the tautomers thereof and the pharmaceuticallyacceptable salts thereof. The compounds of the invention may be presentas a mixture of stereoisomers, individual stereoisomers, or as anoptically active or enantiomerically pure form.

Preferred compounds of the invention are those compounds of formula Iwherein R₁ and R₂ are H. Another group of preferred compounds of theinvention are those compounds of formula I wherein m and n are 1. Alsopreferred are those formula I compounds wherein X is N. A further groupof preferred compounds of the invention are those compounds of formula Iwherein the nitrogen-containing 5-membered or 6-membered heteroaryl ringis attached to the phenyl ring in the 3-position of the phenyl ring;this preferred group of formula I compounds is designated in thespecification and claims as formula Ia. The formula Ia compound is shownbelow.

More preferred compounds of the invention are those compounds of formulaIa wherein the nitrogen-containing heteroaryl ring is a 6-membered ringand is attached to the phenyl ring in the 3-position of said heteroarylring; this more preferred group of formula I compounds is designated inthe specification and claims as formula Ib. Formula Ib is shown below.

Another group of more preferred compounds of the invention are thosecompounds of formula Ib wherein R₁ and R₂ are H. A further group of morepreferred compounds of the invention are those compounds of formula Ibwherein Y is CR₁₁ and R₁ and R₂ are H.

Examples of preferred compounds of formula I include:

-   8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   7-(3-pyrimidin-5-ylphenyl)-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-amine;-   8-[4-fluoro-3-(4-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[3-(5-chloropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   (8S)-8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   (8R)-8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   (8R)-8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   (8S)-8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[3-(4-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-(4-methoxyphenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-(4-methoxyphenyl)-8-(3-pyrimidin-5-ylphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-(4-fluoro-3-pyrimidin-5-ylphenyl)-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-8-(4-methoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-(4-fluoro-3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;-   8-[4-fluoro-3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;    the tautomers thereof; the stereoisomers thereof; or the    pharmaceutically acceptable salts thereof.

Advantageously, the present invention provides a process for thepreparation of a compound of formula I which comprises reacting acompound of formula II wherein Hal is Cl or Br with a compound offormula III wherein W is B(OH)₂, Sn(Bu)₃ or Sn(CH₃)₃ in the presence ofa palladium catalyst and an inorganic base optionally in the presence ofa solvent. The process is shown in flow diagram I, wherein Hal and W areas defined hereinabove.

Flow Diagram I

Palladium catalysts suitable for use in the process of the inventioninclude Pd(0) or Pd(II) catalysts such asdichlorobis(tri-o-tolylphosphine)palladium(II),Pd(OCOCH₃)₂/tri-o-tolylphosphine,tetrakis(triphenylphosphine)palladium(0),

tris(dibenzylideneacetone)dipalladium(0)triphenylphosphine, or the like.

Inorganic bases suitable for use in the inventive process include Na orK hydroxides, carbonates or bicarbonates, preferably Na₂CO₃ or K₂CO₃.

Solvents suitable for use in the inventive process include polar ornon-polar organic solvents such as toluene, diethoxy ethyl ether,dioxane, ethyleneglycol dimethyl ether or any non-reactive organicsolvent which is capable of solubilizing the formula II or formula IIIcompounds.

Compounds of formula II may be prepared using conventional syntheticmethods and, if required, standard separation or isolation techniques.For example, compounds of formula II wherein R₁ and R₂ are H (IIa), maybe prepared by reacting a ketone of formula IV with a phenyl magnesiumbromide of formula V in the presence of a catalyst such as Cul to give a1,1,1-trisubstituted methanol compound of formula VI; reacting saidformula VI methanol sequentially with thionyl chloride and ammonia togive the corresponding methylamine of formula VII; and reacting saidformula VII amine with cyanogen bromide in the presence of acetonitrileto give the desired formula IIa product. The reaction is shown in flowdiagram II wherein Hal is Cl or Br.

Flow Diagram II

Ketones of formula IV may be prepared using conventional techniques, forexample, by reacting a benzoyl halide of formula VIII with an imidazoleor tetrahydropyrimidine of formula IX in the presence of a base such asNaOH, or by oxidizing the appropriate methanol compound of formula Xwith an oxidizing agent such as MnO2. The reactions are shown in flowdiagram III.

Flow Diagram III

Compounds of formula X may be prepared by reacting a benzaldehyde offormula XI with NaHSO₃ and NaCN to give the corresponding cyanomethanolof formula XII; reacting said formula XII compound with ethanol and HClto give the imidate of formula XIII; and reacting said formula XIIIcompound with a diamine of formula XIV to give the desired methanolderivative of formula X. The reaction is shown in flow diagram IVwherein Hal is Cl or Br.

Flow Diagram IV

Compounds of formula IIa may be converted to the corresponding compoundsof formula I wherein R₁ and R₂ are H using the procedure describedhereinabove in flow diagram I.

Compounds of formula I wherein R₁ and R₂ are other than H may beprepared using standard alkylation techniques such as reacting thecompound of formula I wherein R₁ and R₂ are H with an alkyl halide,R₁-Hal, to give the compound of formula I wherein R₂ is H (Id) andoptionally reacting said formula Id compound with a second alkyl halide,R₂-Hal, to give the desired formula I compound wherein R₁ and R₂ areother than H.

Advantageously, the compounds of the invention are useful for thetreatment, prevention or amelioration of a disease or disordercharacterized by elevated β-amyloid deposits or β-amyloid levels in apatient, including Alzheimer's disease, Downs Syndrome, HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch type or otherneurodegenerative or dementia-inducing disorders. Accordingly, thepresent invention provides a method for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient which comprisesproviding said patient with a therapeutically effective amount of acompound of formula I as described hereinabove. The compound may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of a therapeutic agent to apatient in need thereof.

The term “providing” as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

Alternatively, the use of sustained delivery devices may be desirable,in order to avoid the necessity for the patient to take medications on adaily basis. “Sustained delivery” is defined as delaying the release ofan active agent, i.e., a compound of the invention, until afterplacement in a delivery environment, followed by a sustained release ofthe agent at a later time. Those of skill in the art know suitablesustained delivery devices. Examples of suitable sustained deliverydevices include, e.g., hydrogels (see, e.g., U.S. Pat. Nos. 5,266,325;4,959,217; and 5,292,515), an osmotic pump, such as described by Alza(U.S. Pat. Nos. 4,295,987 and 5,273,752) or Merck (European Patent No.314,206), among others; hydrophobic membrane materials, such asethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbablepolymer systems (see, e.g., International Patent Publication No. WO98/44964, Bioxid and Cellomeda; U.S. Pat. Nos. 5,756,127 and 5,854,388);other bioresorbable implant devices have been described as beingcomposed of, for example, polyesters, polyanhydrides, or lacticacid/glycolic acid copolymers (see, e.g., U.S. Pat. No. 5,817,343(Alkermes Inc.)). For use in such sustained delivery devices, thecompounds of the invention may be formulated as described herein.

In another aspect, the invention provides a pharmaceutical kit fordelivery of a product. Suitably, the kit contains packaging or acontainer with the compound formulated for the desired delivery route.For example, if the kit is designed for administration by inhalation, itmay contain a suspension containing a compound of the inventionformulated for aerosol or spray delivery of a predetermined dose byinhalation. Suitably, the kit contains instructions on dosing and aninsert regarding the active agent. Optionally, the kit may furthercontain instructions for monitoring circulating levels of product andmaterials for performing such assays including, e.g., reagents, wellplates, containers, markers or labels, and the like. Such kits arereadily packaged in a manner suitable for treatment of a desiredindication. For example, the kit may also contain instructions for useof the spray pump or other delivery device.

Other suitable components to such kits will be readily apparent to oneof skill in the art, taking into consideration the desired indicationand the delivery route. The doses may be repeated daily, weekly, ormonthly, for a predetermined length of time or as prescribed.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway. Indeed, various modifications of the invention, in addition tothose shown and described herein, will become apparent to those skilledin the art from the examples set forth hereinbelow and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

Unless otherwise noted, all parts are parts by weight. The term NMRdesignates nuclear magnetic resonance. The terms THF and DMF designatetetrahydrofuran and dimethyl formamide, respectively.

EXAMPLE 1 Preparation of 2-(3-Bromobenzoyl)-1 H-imidazole

A solution of imidazole (2.66 g, 39.1 mmol) and triethylamine (Et₃N)8.03 g, 79.4 mmol) in pyridine at 0° C. is treated with 3-bromobenzoylchloride (17.5 g, 79.9 mmol), stirred for 5 min, allowed to warm to roomtemperature for 45 min, treated with an aqueous sodium hydroxidesolution (7.5 N, 20 mL, 150 mmol), heated at reflux temperature for 2 h,cooled to room temperature, diluted with water, further cooled with anice bath for 1 h and filtered. The filtercake is washed with water anddried under vacuum at 50° C. overnight to afford the title compound as alight tan solid, 4.89 g (50% yield), identified by NMR and mass spectralanalyses. ¹H NMR (500 MHz, CDCl₃) δ 10.58 (br s, 1 H), 8.73 (t, J=1.8Hz, 1 H), 8.61 (dt, J=7.8, 1.2 Hz, 1 H), 7.75-7.72 (m, 1 H), 7.42-7.38(m, 2H), 7.32 (s, 1 H); ESI MS m/z 250 [C₁₀H₇BrN₂O+H]⁺.

EXAMPLE 2 Preparation of1-(3-Bromophenyl)-1-(imidazol-2-yl)-1-[4-(trifluoromethoxy)phenyl]methanol

A mixture of magnesium (0.644 g, 87.7 mmol) in THF (13 mL) at 50° C. istreated dropwise with a solution of 1-bromo-4-(trifluoromethoxy)benzene(6.32 g, 26.2 mmol) in THF over a period of 5 min, stirred at 50° C. foran additional 1.5 h, cooled to room temperature, treated with copper(I)iodide (0.041 g, 0.215 mmol) and a solution of 2-(3-bromobenzoyl)-1H-imidazole (2.60 g, 10.4 mmol) in THF, heated at 65° C. overnight,cooled to room temperature and diluted with a 1:1:1 mixture of ethylacetate, water and saturated aqueous ammonium chloride. The phases areseparated and the aqueous phase is extracted with ethyl acetate. Thecombined organic extracts are dried over sodium sulfate, filtered andconcentrated. The resultant residue is purified by flash chromatography(silica, 85:15 to 75:25 hexanes/ethyl acetate as eluent) affords thetitle product as a yellow solid, 3.47 g (81% yield), identified by NMRand mass spectral analyses. ¹H NMR (500 MHz, CDCl₃) δ 8.98 (br s, 1 H),7.55 (t, J=1.6 Hz, 1 H), 7.45 (dt, J=8.1, 1.9 Hz, 1 H), 7.37-7.34 (m,2H), 7.24-7.20 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (br s, 1 H), 6.98(br s, 1 H), 4.30 (br s, 1 H); ESI MS m/z 412 [C₁₇H₁₂BrF₃N₂O₂+H]⁺.

EXAMPLE 3 Preparation of1-(3-Bromophenyl)-1-(imidazol-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine

A mixture of1-(3-bromophenyl)-1-(imidazol-2-yl)-1-[4-(trifluoromethoxy)-phenyl]methanol(1.89 g, 4.57 mmol) and thionyl chloride (2.13 g, 17.9 mmol) in benzeneis heated at 80° C. for 3 h, cooled to room temperature and concentratedin vacuo to dryness. This orange solid residue is dispersed inisopropanol, bubbled with ammonia gas at ice-bath temperature until thesolution is saturated. This ammonia saturated solution is heated in asealed tube at 35° C. overnight, cooled to room temperature,concentrated and partitioned between chloroform (50 mL) and 1 N HCl (50mL). The phases are separated and the organic phase is washed withadditional 1 N HCl. The combined HCl washes are cooled to 0° C.,basified to pH>10 by the addition of solid sodium hydroxide andextracted with chloroform. The combined chloroform extracts are driedover sodium sulfate, filtered and concentrated to afford the titleproduct as a light yellow solid, 1.68 g (89% yield), identified by NMRand mass spectral analyses. ¹H NMR (500 MHz, CDCl₃) δ 9.12 (br s, 1 H),7.51 (t, J=1.2 Hz, 1 H), 7.44-7.41 (m, 1 H), 7.35-7.31 (m, 2H),7.22-7.19 (m, 2H), 7.18-7.15 (m, 2H), 7.15 (t, J=1.5 Hz, 1 H), 6.97 (t,J=1.7 Hz, 1 H), 2.48 (br s, 2H); ESI MS m/z 412 [C₁₇H₁₃BrF₃N₃O+H]⁺.

EXAMPLE 4 Preparation of7-(3-(Bromophenyl)-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine

A mixture of1-(3-bromophenyl)-1-(imidazol-2-yl)-1-[4-(trifluoromethoxy)-phenyl]methylamine(1.67 g, 4.05 mmol) and cyanogen bromide (1.75 g, 16.5 mmol) inacetonitrile is heated at 100° C. in a sealed tube overnight, cooled toroom temperature and concentrated. The resultant residue is purifiedtwice by flash chromatography (silica, 96:4:0.5 methylenechloride/methanol/concentrated ammonium hydroxide, then 85:15 to 50:50hexanes/ethyl acetate as eluent) to afford the title compound as ayellow solid 0.671 g (38% yield), identified by NMR and mass spectralanalyses. ¹H NMR (500 MHz, CDCl₃) δ 7.61 (t, J=1.6 Hz, 1 H), 7.53-7.48(m, 2H), 7.46-7.41 (m, 3H), 7.27-7.22 (m, 4H); ESI MS m/z 437[C₁₈H₁₂BrF₃N₄O+H]⁺.

EXAMPLE 5 Preparation of7-[(3-(Pyrimidin-5-yl)phenyl]-7H-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine

A mixture of7-(3-(bromophenyl)-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine(0.201 g, 0.460 mmol), 5-pyrimidine boronic acid (0.073 g, 0.587 mmol),bis(triphenylphosphino)palladium(II) chloride (0.016 g, 0.0232 mmol),triphenylphosphine (0.012 g, 0.047 mmol) and potassium carbonate (0.189g, 1.37 mmol) in 5:1 dioxane/water is heated at 100° C. for 3.5 h,cooled to room temperature and concentrated. The resultant residue ispurified by flash chromatography (silica, 96:4:0.5 methylenechloride/methanol/concentrated ammonium hydroxide as eluent) to affordthe title compound as an off-white solid, 0.037 g (19% yield), mp120-130° C.; identified by NMR and mass spectral analyses. ¹H NMR (500MHz, CD₃OD) □9.12 (s, 1 H), 9.02 (s, 2H), 7.81 (s, 1 H), 7.67-7.62 (m,2H), 7.56-7.51 (m, 3H), 7.47 (d, J=1.1 Hz, 1 H), 7.27 (d, J=1.5 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H); IR (ATR) 3143, 1672, 1505, 1443, 1414, 1253,1216, 1159, 791, 723 cm⁻¹; ESI MS m/z 437 [C₂₂H₁₅F₃N₆O+H]⁺

EXAMPLE 6 Preparation of 1-(3-Bromo-4-fluorophenyl)-1-cyanomethanol

A solution of sodium bisulfite (28.3 g, 271 mmol) in water at 50° C. istreated with 3-bromo-4-fluorobenzaldehyde (45.8 g, 225 mmol), stirred at50° C. for 2 h, cooled with an ice bath, diluted with ether, treateddropwise with an aqueous solution of sodium cyanide (12.2 g, 248 mmol)over a period of 30 min and stirred at room temperature overnight. Thereaction mixture is separated, and the aqueous phase is extracted withether. The extracts are combined with the organic phase, washed withbrine, dried over magnesium sulfate and concentrated to dryness toafford the title compound as a clear oil, 47.6 g (92% yield), identifiedby NMR analysis. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (m, 1 H), 7.47 (m, 1 H),7.23 (m, 1 H), 5.54 (m, 1 H), 3.19 (m, 1 H).

EXAMPLE 7 Preparation of Ethyl2-(3-Bromo-4-fluorophenyl)-2-hydroxyethanimidoate Hydrochloride

A solution of 1-(3-bromo-4-fluorophenyl)-1-cyanomethanol (47.5 g, 206mmol) and ethanol (10.9 g, 237 mmol) in ether is cooled with an ice bathand treated dropwise with HCl (258 mL of a 1.0 M solution in diethylether, 258 mmol) over a period of 40 min., stirred at ice-bathtemperature for 2 h, stored at 0° C. for 6 days, warmed to roomtemperature, diluted with hexanes and filtered. The filtercake is driedto afford the title compound as a white solid, 39.8 g (62% yield),identified by NMR and mass spectral analyses. The title compound is amixture of E and Z isomers. ¹H NMR (300 MHz, CD₃OD) δ 7.78 (m, 1 H),7.49 (m, 1 H), 7.28 (m, 1 H), 5.54 and 5.17 (2m, 1 H), 4.45 and 4.15(2m, 2H), 1.38 and 1.20 (2t, 3H); ESI MS m/z 261 [C₁₀H₁₁BrFNO₂+H]⁺

EXAMPLE 8 Preparation of1-(3-Bromo-4-fluorophenyl)-1-(2-tetrahydropyrimidinyl)methanol

A mixture of ethyl 2-(3-bromo-4-fluorophenyl)-2-hydroxyethanimidoateHydrochloride (39.8 g, 127 mmol) and 1,3-diaminopropane (9.43 g, 127mmol) in ethanol is heated at 120° C. in a sealed tube overnight, cooledto room temperature, concentrated to remove the solvent, diluted withwater, stirred vigorously for 1 h and filtered. The filtrate is cooledwith an ice bath, made strongly basic with 1 N NaOH, cooled for 1 h inan ice bath and filtered. The filtercake is dried to afford the titlecompound as a white solid 23.4 g (64% yield), identified by NMR and massspectral analyses. ¹H NMR (500 MHz, CDCl₃) δ 7.59 (m, 1 H), 7.30 (m, 1H), 7.10 (t, J=8.4 Hz, 1 H), 4.79 (s, 1 H), 3.35 (m, 4H), 1.76 (m, 2H);ESI MS m/z 287 [C₁₁H₁₂BrFN₂O+H]⁺.

EXAMPLE 9 Preparation of2-(3-Bromo-4-fluorobenzoyl)-2,3,4,5-tetrahydropyrimidine

A mixture of1-(3-bromo-4-fluorophenyl)-1-(2-tetrahydropyrimidinyl)methanol (23.4 g,81.5 mmol) and manganese dioxide (70.8 g, 815 mmol) in methylenechloride is stirred at room temperature for 3 days and filtered throughdiatomaceous earth. The filtercake is washed with chloroform. Thefiltrates are combined and concentrated to dryness to afford the titlecompound as a yellow-green solid, 18.9 g (81% yield), identified by NMRand mass spectral analyses. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (m, 1 H),8.23 (m, 1 H), 7.15 (t, J=8.4 Hz, 1 H), 6.10 (br s, 1 H), 3.65 (br s,2H), 3.41 (br s, 2H), 1.83 (m, 2H); ESI MS m/z 284 [C₁₁H₁₀BrFN₂O+H]⁺.

EXAMPLE 10 Preparation of1-(3-Bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methanol

A mixture of magnesium (2.13 g, 87.7 mmol) in THF at 50° C. is treateddropwise with a solution of 1-bromo-4-(trifluoromethoxy)benzene (21.1 g,87.7 mmol) in THF over a period of 20 min., stirred at 50° C. for anadditional 1.5 h, cooled to room temperature, treated with copper(I)iodide (0.13 g, 0.70 mmol) and a solution of2-(3-bromo-4-fluorobenzoyl)-2,3,4,5-tetrahydropyrimidine (10.0 g, 14.9mmol) in THF, heated at 65° C. overnight, cooled to room temperature anddiluted with ethyl acetate and saturated aqueous ammonium chloride. Thephases are separated. The organic phase is washed sequentially withwater and brine, dried over sodium sulfate, and concentrated to afford18.5 g of a brown oil. The oil is purified by flash chromatography(silica, 90:10:0.5 methylene chloride/methanol/concentrated ammoniumhydroxide as eluent) to afford the title compound as a yellow oil, 10.0g (64% yield), identified by NMR and mass spectral analyses. ¹H NMR (300MHz, CDCl₃) δ 7.60 (dd, J=6.4, 2.3 Hz, 1 H), 7.41 (dd, J=6.9, 2.0 Hz,2H), 7.28-7.20 (m, 3H), 7.10 (t, J=8.3 Hz, 1 H), 3.50 (m, 6H), 1.96 (m,2H); ESI MS m/z 447 [C₁₈H₁₅BrF₄N₂O₂+H]⁺.

EXAMPLE 11 Preparation of1-(3-Bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine

A mixture of1-(3-bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methanol(4.60 g, 10.3 mmol) and thionyl chloride (12.2 g, 103 mmol) in tolueneis heated at 110° C. overnight, cooled to room temperature andconcentrated to dryness to give a tan solid residue. The residue isdispersed in isopropanol and bubbled through with ammonia gas until themixture is saturated with ammonia. The saturated mixture is heated in asealed tube at 45° C. overnight, cooled to room temperature andconcentrated. The resultant residue is partitioned between chloroformand 1 N NaOH. The aqueous phase is separated and extracted withchloroform. The extracts are combined with the organic phase, dried overpotassium carbonate and concentrated to afford the title compound as adark oil, 0.89 g (>100%, ˜80% purity), identified by NMR and massspectral analyses. ¹H NMR (300 MHz, CDCl₃) δ 7.65 (m, 1 H), 7.41-7.303(m, 36H), 3.41 (br s, 4H), 2.32 (br s, 2H), 1.77 (m, 2H); ESI MS m/z 446[C₁₈H₁₆BrF₄N₃O+H]⁺.

EXAMPLE 12 Preparation of8-(3-Bromo-4-fluorophenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine

A mixture of1-(3-bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methylamine(0.85 g, ˜80% purity, ˜1.52 mmol) and cyanogen bromide (0.81 g, 7.62mmol) in acetonitrile is stirred at room temperature for 45 min, heatedat 100° C. in a sealed tube overnight, cooled to room temperature andconcentrated. The resultant residue is purified by flash chromatography(silica, 95:5:0.25 methylene chloride/methanol/concentrated ammoniumhydroxide as eluent) to afford the title compound as a tan solid, 0.26 g(36% yield), identified by NMR and mass spectral analyses. ¹H NMR (300MHz, CDCl₃) δ 7.74 (dd, J=6.7, 2.3 Hz, 1 H), 7.49 (dd, J=6.7, 2.1 Hz,2H), 7.38 (m, 1 H), 7.13 (d, J=8.1 Hz, 2H), 7.03 (t, J=8.5 Hz, 1 H),3.58 (m, 4 H), 1.86 (m, 2H); ESI MS m/z 471 [C₁₉H₁₅BrF₄N₄O+H]⁺.

EXAMPLE 13 Preparation of8-{[(4-Fluoro-3-pyrimidin-5-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-yl}amine

A mixture of8-(3-bromo-4-fluorophenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine(0.26 g, 0.552 mmol), 5-pyrimidine boronic acid (0.082 g, 0.662 mmol),tetra(kistriphenylphosphino)-palladium(0) (0.032 g, 0.0276 mmol) andpotassium carbonate (0.23 g, 1.65 mmol) in 5:1 dioxane/water is heatedat 100° C. for 1 h, treated with additionaltetra(kistriphenylphosphino)palladium(0) (0.032 g, 0.0276 mmol), heatedat 100° C. for 3.5 h, cooled to room temperature and concentrated. Theresultant residue is purified by flash chromatography (silica, 95:5:0.25methylene chloride/methanol/ concentrated ammonium hydroxide as eluent)to afford the title compound as an off-white solid, 0.079 g (30% yield),mp 105-115° C., identified by NMR and mass spectral analyses. ¹H NMR(300 MHz, CD₃OD) □9.14 (s, 1 H), 8.97 (s, 2H), 7.55 (m, 2H), 7.43 (dd,J=6.8, 2.1 Hz, 2H), 7.21-7.31 (m, 3H), 3.69 (m, 2H), 3.50 (m, 2H), 1.87(m, 2H); ESI MS m/z 471 [C₂₃H₁₈ F₄N₆O+H]⁺;

EXAMPLE 14 Preparation of{8-[4-Fluoro-3-(5-fluoropyrimidin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-yl}amine

A mixture of8-(3-bromo-4-fluorophenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine(0.075 g, 0.159 mmol), 3-fluoro-5-(tributylstannyl)pyridine (0.092 g,0.239 mmol), and dichlorobis(triphenylphos-phine)palladium(II) (0.006 g,0.008 mmol) in DMF is degassed, heated at 150° C. in a sealed tube for1.5 h, cooled to room temperature and diluted with ethyl acetate (50 mL)and 5% aqueous LiCl. The reaction mixture is separated. The organicphase is washed with 5% aqueous LiCl, dried over sodium sulfate andconcentrated. The resultant residue is purified by flash chromatography(silica, 95:5:0.25 methylene chloride/methanol/ concentrated ammoniumhydroxide as eluent) to afford the title product as a white solid, 0.043g (56% yield), mp 94-105° C.; identified by NMR and mass spectralanalyses. ¹H NMR (300 MHz, CD₃OD) □8.56 (d, J=1.3 Hz, 1 H), 8.47 (d,J=2.6 Hz, 1 H), 7.83 (d, J=9.7 Hz, 1 H), 7.54-7.44 (m, 4H), 7.41-7.21(m, 3H), 3.69 (m, 2H), 3.50 (m, 2H), 1.87 (m, 2H); ESI MS m/z 488[C₂₄H₁₈ F₅N₅O+H]⁺;

EXAMPLES 15-28 Preparation of DiphenylimidazopyrimidinylamineDerivatives

Using essentially the same procedures described in Examples 5, 13 and 14hereinabove and employing the appropriate azacyclic reagent wherein W isB(OH)₂ or Sn(n-Bu)₃, the compounds on Table I were obtained andidentified by NMR and mass spectral analyses.

TABLE I

Ex. mp No. R5 R6 R8 R10 X ° C. 15 OCF₃ H 4-F 2-F C—H  99-122 16 OCF₃ H HH N 214-218 17 OCF₃ H H 2-F C—H 105-115 18 OCF₃ H 4-F 6-F C—H 110-115 19OCF₃ H H H C—F 112-118 20 OCF₃ H H H C—Cl 112-116 21 OCH₃ H H 2-F C—H117-121 22 OCH₃ H H H N 136-140 23 OCH₃ H 4-F H N 122 24 OCH₃ H 4-F 2-FC—H 115 25 OC₂H₅ OC₂H₅ H 2-F C—H 202-208 26 OCHF₂ H H 4-F C—H  81-92 27OCF₃ H H 4-F C—H  83-97 28 OCF₃ H H 2-F C—F  94-102

EXAMPLE 29 Preparation of8-(3-Pyrimidin-5-yl-phenyl)-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-yl-cyanamide

A mixture of ethylene glycol dimethyl ether,tris(dibenzylideneacetone)-dipalladium(0) (0.014 g, 16.0 μmol),triphenylphosphine (0.008 g, 32.0 μmol) under a nitrogen atmosphere isstirred for 5 min., treated with 2 (0.153 g, 0.320 mmol),pyrimidine-5-boronic acid (0.047 g, 0.380 mmol), sodium carbonate (0.101g, 0.96 mmol) and water (2 mL), heated at 85° C. for 1 hr, cooled toroom temperature and concentrated. the resultant residue is purified byflash chromatography (silica, 97.5:2.5:0.5 methylenechloride/methanol/concentrated ammonium hydroxide as eluent) to affordthe title compound as a white solid, 0.130 g (85% yield), mp 227-231°C.; identified by NMR and mass spectral analyses. ¹H NMR (500 MHz,CD₃OD) δ 9.13 (s, 1 H), 9.02 (s, 2H), 7.77 (d, J=7.5 Hz, 1 H), 7.71 (s,1 H), 7.62 (dd, J=7.9, 7.6 Hz, 1 H) 7.57 (d, J=8.0 Hz, 1 H), 7.50 (d,J=8.9 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 1.89(m, 2H); IR (ATR) 3106, 2187, 1622, 1500, 1412, 1256, 1218, 1159 cm³¹ ¹;ESI MS m/z 478 [C₂₄H₁₈F₃N₇O+H

EXAMPLE 30 Preparation of(8R)-8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(A) and(8S)-8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(B)

A racemic mixture of8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine_(0.740g, 1.57 mmol) is placed on a Chiralpak AD 5×50 cm column (90:10:0.1heptane/ethanol/diethylamine as eluent). The second eluting peak(t_(R)=26 min) is collected and concentrated to a pale yellow oil. Theoil residue is re-dissolved in a minimal amount of methylene chloride,triturated with hexanes and filtered. The filtercake is dried undervacuum for 24 h to afford the title product A as an off-white solid,0.299 g, mp 126-131° C.; [

]²⁵ _(D): −11.6° (c=0.5 in MeOH); identified by NMR, infrared and massspectral analyses. ¹H NMR (500 MHz, CD₃OD)

8.16 (dd, J=4.8, 1.1 Hz, 1 H), 8.03-7.98 (m, 1 H), 7.58 (s, 1 H),7.55-7.52 (m, 1 H), 7.49-7.45 (m, 3H), 7.44-7.41 (m, 1 H), 7.40-7.37 (m,1 H), 7.23 (d, J=8.2 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.49 (t, J=5.4 Hz,2H), 1.90-1.85 (m, 2H); IR (ATR) 3062, 2954, 1654, 1602, 1504, 1434,1251, 1216, 1159, 791 cm⁻¹; ESI MS m/z 470 [C₂₄H₁₉F₄N₅O+H]⁺;

The first eluting peak (t_(R)=19 min) is collected and concentrated to apale yellow oil. The oil residue is re-dissolved in a minimal amount ofmethylene chloride, triturated with hexanes and filtered. The filtercakeis dried under vacuum for 24 h to afford the title product B as anoff-white solid, 0.315 g, mp 124-128° C.; [

]²⁵ _(D): +12.6° C. (c =0.5 in MeOH); identified by NMR, infrared andmass spectral analyses. ¹H NMR (500 MHz, CD₃OD)

8.16 (dd, J=4.8, 1.1 Hz, 1 H), 8.03-7.98 (m, 1 H), 7.58 (s, 1 H),7.55-7.52 (m, 1 H), 7.49-7.45 (m, 3H), 7.44-7.41 (m, 1 H), 7.40-7.37 (m,1 H), 7.23 (d, J=8.2 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.49 (t, J=5.4 Hz,2H), 1.90-1.85 (m, 2H); IR (ATR) 3064, 2947,1653, 1602, 1504, 1434,1251, 1216, 1158, 791 cm⁻¹; ESI MS m/z 470 [C₂₄H₁₉F₄N₅O+H]

EXAMPLE 31 Preparation of(8R)-8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(A) and(8S)-8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(B)

A racemic mixture of8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine_(2.0g, 1.57 mmol) is placed on a Chiralpak AD 5×50 cm column (90:10:0.1heptane/ethanol/diethylamine as eluent). The first eluting peak(t_(R)=34 min) is collected and concentrated to give a pale yellow oil.The oil is re-dissolved in a minimal amount of methylene chloride,triturated with hexanes and filtered. The filtercake is dried undervacuum for 24 h to afford the title compound A as an off-white solid,0.815 g, mp 178-186° C.; [

]²⁵ _(D): −14.7° (c=0.50 in MeOH); identified by NMR, infrared and massspectral analyses. ¹H NMR (500 MHz, CD₃OD)

9.12 (s, 1H), 9.02 (s, 2H), 7.70-7.67 (m, 2H), 7.57-7.51 (m, 2H),7.48-7.44 (m, 2H), 7.26 (d, J=8.7 Hz, 2H), 3.73 (t, J=6.3 Hz, 2H),3.55-3.52 (m, 2H), 1.92-1.88 (m, 2H); IR (ATR) 3040, 2956, 2859, 1655,1504, 1413, 1253, 1160, 786 cm⁻¹; ESI MS m/z 453 [C₂₃H₁₉F₃N₅O+H]⁺;

The second eluting peak (t_(R)=46 min) is collected and concentrated togive a pale yellow oil. The oil residue is re-dissolved in a minimalamount of methylene chloride, and then triturated with hexanes andfiltered. The filtercake is dried under vacuum for 24 h to afford thetitle compound B as an off-white solid, 0.798 g, mp 180-186° C.; [

]²⁵ _(D): +9.7° (c=0.51 in MeOH), identified by NMR, infrared and massspectral analyses. ¹H NMR (500 MHz, CD₃OD)

9.13 (s, 1 H), 9.02 (s, 2H), 7.73-7.69 (m, 2H), 7.58-7.51 (m, 2H),7.49-7.46 (m, 2H), 7.29-7.26 (m, 2H), 3.76 (t, J=6.3 Hz, 2H), 3.57-3.55(m, 2H), 1.93-1.90 (m, 2H); IR (ATR) 3040, 2955, 1655, 1553, 1505, 1413,1253, 1201, 1162, 786 cm⁻¹; ESI MS m/z 453 [C₂₃H₁₉F₃N₅O+H]⁺

EXAMPLE 32 Preparation of(8S)-8-[3-(5-Chloropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine[A] and(8R)-8-[3-(5-Chloropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine[B]

A racemic mixture of8-[3-(5-chloropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(1.73 g) was separated into its enantiomers using a Chiralpak AD 5×50 cmcolumn (90:10:0.1 heptane/ethanol/diethylamine) to afford the titleS-isomer (A) as an off-white solid, mp 104-116° C.; [α]²⁵ _(D): −8.6°(c=0.51% in MeOH); ¹H NMR (500 MHz, CD₃OD) δ 8.69 (d, J=1.9 Hz, 1 H),8.53 (d, J=2.2 Hz, 1 H), 8.11 (t, J=2.1 Hz, 1 H), 7.69-7.67 (m, 1 H),7.65 (t, J=1.7 Hz, 1 H), 7.54 (t, J=7.6 Hz, 1 H), 7.51-7.45 (m, 3H),7.29 (d, J=8.3 Hz, 2H), 3.77 (t, J=5.9 Hz, 2H), 3.58-3.55 (m, 2H),1.97-1.92 (m, 2H); ESI MS m/z 486 [C₂₄H₁₉CIF₃N₅O+H]⁺; and the titleR-isomer (B) as an off-white solid, mp 114-118° C.; [α]²⁵ _(D): +13.3°(c=0.53% in MeOH); ¹H NMR (500 MHz, CD₃OD) □ 8.69 (d, J=1.9 Hz, 1 H),8.54 (d, J=2.3 Hz, 1 H), 8.11 (t, J=2.1 Hz, 1 H), 7.70-7.67 (m, 1 H),7.65 (t, J=1.6 Hz, 1 H), 7.55 (t, J=7.7 Hz, 1 H), 7.52-7.46 (m, 3H),7.29 (d, J=8.2 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.59-3.56 (m, 2H),1.95-1.90 (m, 2H); ESI MS m/z 486 [C₂₄H₁₉CIF₃N₅O+H]⁺.

EXAMPLE 33 Preparation of(8S)-8-[3-(4-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine[A] and(8R)-8-[3-(4-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine[B]

A racemic mixture of8-[3-(4-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine(1.89 g) was separated into its enantiomers using a Chiralpak AD 5×50 cmcolumn (93:7:0.1 heptane/ethanol/ diethylamine) to give the titleS-isomer (A) as an off-white solid (0.755 g), mp 171° C.; [α]²⁵ _(D):+10.6° (c=0.5% in MeOH); ¹H NMR (500 MHz, CD₃OD) δ 8.63 (d, J=10.0 Hz, 1H), 8.52 (dd, J=7.3, 5.7 Hz, 1 H), 7.57-7.52 (m, 2H), 7.51-7.45 (m, 4H),7.32 (dd, J=10.3, 5.7 Hz, 1 H), 7.24 (d, J=8.1 Hz, 2H), 3.71 (t, J=5.9Hz, 2H), 3.50 (t, J=5.5 Hz, 2H), 1.90-1.85 (m, 2H); ESI MS m/z 470[C₂₄H₁₉F₄N₅O+H]⁺; and the title R-isomer (B) as an off-white solid(0.675 g), mp 115-116° C.; [α]²⁵ _(D): −10.9° (c =0.5% in MeOH); ¹H NMR(500 MHz, CD₃OD) □ 8.63 (d, J=10.1 Hz, 1 H), 8.53 (dd, J=7.3, 5.7 Hz, 1H), 7.57-7.54 (m, 2H), 7.53-7.45 (m, 4H), 7.32 (dd, J=10.3, 5.7 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 3.73 (t, J=6.0 Hz, 2H), 3.52 (t, J=5.7 Hz,2H), 1.90 (quintet, J=6.3 Hz, 2H; ESI MS m/z 470 [C₂₄H₁₉F₄N₅O+H]⁺.

EXAMPLE 34 Preparation of 8-[3-(2-Fluoro1-oxy-pyridin-3-yl)-phenyl]-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

Step a) Preparation of Compound 2

A mixture of 1 (0.580 g, 1.24 mmol), di-tert-butyl dicarbonate (0.670 g,3.10 mmol) and 4-dimethylaminopyridine (0.151 g, 1.24 mmol) intetrahydrofuran (15 mL) was stirred at room temperature for 1 h. Themixture was then diluted with methylene chloride (75 mL), washed with 1M citric acid (25 mL), water (25 mL) and brine (25 mL), dried oversodium sulfate, filtered and concentrated to afford 2 (0.74 g, 89%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=7.1 Hz, 1 H), 7.84(m, 1 H), 7.73 (s, 1 H), 7.60-7.55 (m, 3H), 7.51-7.47 (m, 1 H), 7.42 (t,J=7.8 Hz, 1 H), 7.26-7.22 (m, 1 H), 7.17 (d, J=8.1 Hz, 2H), 3.66-3.61(m, 2H), 3.50 (t, J=6.0 Hz, 2H), 1.88-1.83 (m, 2H), 1.33 (s, 18H); ESIMS m/z 670 [C₃₄H₃₅F₄N₅O₅+H]⁺.

Step b) Preparation of Compound 3

Trifluoroacetic anhydride (0.365 g, 1.74 mmol) was added dropwise to astirred suspension of urea-hydrogen peroxide complex (0.169 g, 1.80mmol) in methylene chloride (15 mL) at 0° C. The mixture was stirred for5 min and then a solution of 2 (0.200 g, 0.29 mmol) in methylenechloride (10 mL) was added dropwise. The reaction was warmed to roomtemperature and then heated at 40° C. for 45 min. After this time, thereaction was cooled to room temperature, diluted with methylene chloride(50 mL) and washed with saturated aqueous sodium bicarbonate (2×20 mL)and brine (20 mL), dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography (silica, 97.5:2.5 to 95:5 methylenechloride/methanol) afforded 3 (0.086 g, 41%) as a colorless oil: ¹H NMR(300 MHz, CDCl₃) δ 8.25 (dt, J=6.3, 1.5 Hz, 1 H), 7.73 (s, 1 H),7.68-7.62 (m, 1 H), 7.57 (d, J=6.9 Hz, 2H), 7.49-7.43 (m, 2H), 7.40-7.33(m, 1 H), 7.20-7.13 (m, 3H), 3.64 (t, J=5.4 Hz, 2H), 3.50 (t, J=5.8 Hz,2H), 1.90-1.81 (m, 2H), 1.45 (s, 18H); ESI MS m/z 686 [C₃₄H₃₅F₄N₅O₆+H]⁺.

Step c Preparation of 8-[3-(2-Fluoro1-oxy-pyridin-3-yl)-phenyl]-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

A mixture of 3 (0.08 g, 0.11 mmol) and 4 M HCl/dioxane (5 mL) wasstirred at room temperature for 20 h. The solvents were evaporated andthe residue diluted with saturated aqueous sodium bicarbonate (15 mL)and methylene chloride (20 mL). The layers were separated and theorganic layer washed with brine (10 mL), dried over sodium sulfate,filtered and concentrated. The crude product was purified by preparativeHPLC. The appropriate fractions were combined, concentrated, thenneutralized with saturated aqueous sodium bicarbonate (10 mL) andextracted with methylene chloride (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over sodium sulfate, filtered andconcentrated. The residue was freeze dried from acetonitrile/water (8mL, 1:1) to afford the title product as a white solid, 0.018 g (32%yield), ¹H NMR (300 MHz, CDCl₃) δ 8.24 (dt, J=6.3, 1.6 Hz, 1 H), 7.74(s, 1 H), 7.62-7.53 (m, 3H), 7.48-7.32 (m, 3H), 7.20-7.12 (m, 3H), 3.66(t, J=5.9 Hz, 2H), 3.60 (t, J=5.5 Hz, 2H), 1.88 (t, J=5.7 Hz, 2H); ESIMS m/z 486 [C₂₄H₁₉F₄N₅O₂+H]⁺.

EXAMPLE 35 Preparation of7-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine

Step a) Preparation of Compound 2

A mixture of magnesium (0.60 g, 24.7 mmol) in THF (6 mL) was heated to50° C. and treated dropwise with a solution of1-bromo-4-(trifluoromethoxy)-benzene (5.96 g, 24.7 mmol) in THF (18 mL)over a period of 10 min. After stirring at 50° C. for an additional 1.5h, the mixture was cooled to room temperature and treated with asolution of 1 (3.0 g, 16.5 mmol) in THF (12 mL). The mixture was thenreheated to 65° C. for 1 h. After this time, the reaction mixture wascooled to room temperature and poured onto a solution of saturatedaqueous ammonium chloride (20 mL) and conc. ammonium hydroxide (20 mL)at −15° C. and stirred for 5 min. This mixture was then filtered througha pad of celite 521 with ether (100 mL). The organic layer in thefiltrate was separated, washed with brine (50 mL), dried over magnesiumsulfate, filtered and concentrated to afford the crude imine (3.90 g,68%) as an amber oil. A solution of this crude imine (3.90 g, 11.3 mmol)in MeOH (20 mL) was cooled with an ice bath and treated with sodiumborohydride (0.86 g, 22.7 mmol). The cooling bath was removed and themixture stirred at room temperature for 3 h. After this time the mixturewas concentrated and partitioned between 1 N NaOH (100 mL) and methylenechloride (100 mL). The organic layer was separated and washed with brine(100 mL), dried over potassium carbonate, filtered and concentrated.Purification by flash chromatography (silica, 1:4 ethyl acetate/hexanes)afforded 2 (1.98 g, 34% over 2 steps): ¹H NMR (300 MHz, CDCl₃) δ 7.56(t, J=1.7 Hz, 1 H), 7.40-7.15 (m, 7H), 5.19 (s, 1 H); ESI MS m/z 329[C₁₈H₁₅BrF₄N₂O₂—NH₂+H]⁺.

Step b) Preparation of Compound 3

A mixture of 2 (0.66 g, 1.91 mmol) in methylene chloride (2 mL) andsaturated aqueous sodium bicarbonate (2 mL) was cooled with an ice bath,treated with thiophosgene (0.24 g, 2.10 mmol) and stirred vigorously for30 min. The organic layer was separated, washed with brine (2 mL), driedover sodium sulfate and concentrated to afford 3 (0.74 g, 100%) as ayellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.22 (m, 8H), 5.97 (s, 1 H).

Step c) Preparation of Compound 4

To a mixture of potassium t-butoxide (0.070 g, 0.623 mmol) intetrahydrofuran (2 mL) at −78° C. was added dropwise a solution of 3(0.220 g, 0.567 mmol) and carbon disulfide (0.065 g, 0.850 mmol) intetrahydrofuran (3 mL). The reaction was stirred at −78° C. for 0.5 h,then warmed to room temperature slowly and stirred overnight at roomtemperature. The reaction was then diluted with ethyl acetate (50 mL)and water (10 mL). The organic layer was separated, washed with brine(10 mL), dried over sodium sulfate and concentrated, to afford 4 (0.26g, 99%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.86-7.10 (m, 8H),3.70 (s, br, 1H).

Step d) Preparation of Compound 5

A solution of 4 (0.850 g, 1.83 mmol) and ethylenediamine (0.330 g, 5.49mmol) in ethanol (15 mL) was heated overnight at 70° C. The reaction wascooled to room temperature and concentrated. Purification by flashchromatography (silica, 1:4 ethyl acetate/hexanes) afforded 5 (0.45 g,54%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.50 (s, 1 H),7.59-7.19 (m, 8H), 4.46 (t, J=8.5 Hz, 2H), 3.87 (t, J=8.5 Hz, 2H); ESIMS m/z 456 [C₁₈H₁₃BrF₃N₃OS+H]⁺.

Step e) Preparation of Compound 6

A mixture of 5 (0.200 g, 0.438 mmol) and t-butyl hydroperoxide (0.79 gof a 70% solution in water, 8.80 mmol) in methanol (20 mL) andconcentrated aqueous ammonium hydroxide (4 mL) was stirred overnight atroom temperature. The reaction was then concentrated. Purification byflash chromatography (silica, 95:5:0.25 methylenechloride/methanol/concentrated ammonium hydroxide) afforded 6 (0.156 g,81%) as a white solid: ¹H NMR (300 MHz, CD₃OD) δ 7.58 (t, J=1.5 Hz,1 H),7.49-7.44 (m, 3H), 7.36 (dt, J=7.8, 1.5 Hz, 1 H), 7.29-7.23 (m, 3H),4.41 (t, J=8.7 Hz, 2H), 3.75 (t, J=8.7 Hz, 2H); ESI MS m/z 440[C₁₈H₁₄BrF₃N₄O+H]⁺.

Step f) Preparation of7-[3-(2-fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine

A mixture of 6 (0.070 g, 0.159 mmol), triphenylphosphine (0.004 g, 0.016mmol), bis(dibenzylideneacetone)palladium(0) (0.007 g, 0.008 mmol),sodium carbonate (0.051 g, 0.478 mmol) and 2-fluoro-3-boronic acid(0.040 g, 0.287 mmol) in ethylene glycol dimethyl ether (6 mL) and water(2 mL) was degassed and heated at 80° C. for 2.5 h. The mixture wascooled to room temperature and diluted with ethyl acetate (100 mL) andwater (50 mL). The organic layer was separated, washed with brine (20mL), dried over sodium sulfate, filtered, and concentrated. Purificationby flash chromatography (silica, 93:7:0.25 methylenechloride/methanol/concentrated ammonium hydroxide) and then bypreparative HPLC afforded a mixture of starting material and product. Amixture of this material (0.032 g, 0.073 mmol), triphenylphosphine(0.002 g, 0.007 mmol), bis(dibenzylideneacetone)palladium(0) (0.003 g,0.004 mmol), sodium carbonate (0.023 g, 0.220 mmol) and2-fluoro-3-boronic acid (0.019 g, 0.131 mmol) in ethylene glycoldimethyl ether (6 mL) and water (2 mL) was degassed and heated at 80° C.overnight. The organic layer was separated, washed with brine (20 mL),dried over sodium sulfate, filtered, and concentrated. Purification byflash chromatography (silica, 95:5:0.25 methylenechloride/methanol/concentrated ammonium hydroxide) afforded the titleproduct as a white solid, 0.030 g (41% yield), mp 95-100 ° C.; ¹H NMR(500 MHz, CD₃OD) 8.17 (dt, J=4.5, 1.0 Hz, 1 H), 8.02 (ddd, J=7.5, 2.0,2.0 Hz, 1 H), 7.64-7.38 (m, 9H), 7.26 (d, J=8.0 Hz, 2H), 4.43 (d, J=9.0Hz, 2H), 3.78 (d, J=9.0 Hz, 2H); IR (ATR) 2925, 1644, 1601, 1504, 1450,1434, 1400, 1250, 1211, 1157, 1010, 966, 791 cm⁻¹; ESI MS m/z 456[C₂₃H₁₇F₄N₅O+H]⁺.

EXAMPLE 36 Preparation of9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluoromethoxy-phenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine

Step a) Preparation of Compound 2

A solution of 1 (0.50 g, 1.08 mmol) and 1,4-diamino propane (0.28 g,3.23 mmol) in ethanol was heated at 70° C. for 18 h, cooled to roomtemperature and concentrated in vacuo. The concentrate was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith brine, dried over magnesium sulfate and concentrated. Purificationof the resultant residue by flash chromatography (silica, 1:4 ethylacetate/hexanes) afforded 2 (0.22 g, 42%) as a white foam: ¹H NMR (300MHz, CDCl₃) δ 7.47 (m, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.25-7.18 (m, 4H),4.15 (m, 2H), 3.81 (m, 2H), 1.99 (m, 4H); ESI MS m/z 484[C₂₀H₁₇BrF₃N₃OS+H]⁺.

Step b) Preparation of Compound 3

A mixture of 2 (0.22 g, 0.454 mmol) and t-butyl hydroperoxide (1.17 g ofa 70% solution in water, 9.08 mmol) in methanol and concentrated aqueousammonium hydroxide (4.4 mL) was stirred overnight at room temperature,treated with 10% aqueous sodium thiosulfate (30 mL) and concentrated toremove most of the methanol. The remaining aqueous mixture was extractedwith methylene chloride. The methylene chloride extracts were combined,washed with brine, dried over magnesium sulfate, and concentrated.Purification of the resultant residue by flash chromatography (silica,95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide)afforded 3 (0.136 g, 65%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ7.63 (t, J=1.7 Hz, 1 H), 7.46 (dd, J=6.8, 2.0 Hz, 2H), 7.39-7.33 (m,2H), 7.19-7.12 (m, 3H), 3.73 (m, 2H), 3.57 (m, 2H), 1.93 (m, 4H); ESI MSm/z 467 [C₂₀H₁₈BrF₃N₄O+H]⁺.

Step c) Preparation of9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluorometh-oxyphenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine

A mixture of 3 (0.065 g, 0.139 mmol), 2-fluoropyridine-3-boronic acid(0.035 g, 0.250 mmol), bis(triphenylphosphino)palladium(II) chloride(0.0049 g, 0.007 mmol), triphenylphosphine (0.0036 g, 0.014 mmol) andsodium carbonate (0.044 g, 0.417 mmol) in 3:1 DME/water was heated atreflux temperature for 1 h, cooled to room temperature and diluted withethyl acetate and water. The organic layer was separated, washed withbrine, dried over magnesium sulfate and concentrated. Purification ofthe resultant residue by flash chromatography (silica, 95:5:0.25methylene chloride/methanol/concentrated ammonium hydroxide) afforded0.049 g of a white foam. This material was freeze dried from 2:1acetonitrile/water to afford the title product as a white solid, 0.041 g(62% yield), mp 88-97° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.16 (d, J=4.3 Hz,1 H), 8.00 (m, 1 H), 7.59-7.37 (m, 7H), 7.22 (d, J=8.7 Hz, 2H),3.73-3.64 (m, 4H), 1.96 (m, 4H); ESI MS m/z 484 [C₂₅H₂₁F₄N₅O+H]⁺;

EXAMPLE 37 Preparation of1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine

Step a) Preparation of Compound 2

A solution of 1 (0.50 g, 1.08 mmol) and 1,5-diamino pentane (0.33 g,3.23 mmol) in ethanol was heated at 70° C. for 5 h, then at 100° C. for17 h and finally at 120° C. for 6 h. The reaction was cooled to roomtemperature, concentrated and the concentrate was partitioned betweenethyl acetate and water. The organic layer was separated, washed with,dried over magnesium sulfate and concentrated. Purification of theresultant residue by flash chromatography (silica, 1:4 ethylacetate/hexanes) afforded 2 (0.153 g, 28%) as a white foam: ¹H NMR (300MHz, CDCl₃) δ 7.54 (t, J=1.7 Hz, 1 H)), 7.50-7.19 (m, 7H), 4.45 (t,J=6.6 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 1.96-1.86 (m, 4H), 1.48-1.44 (m,2H); ESI MS m/z 498 [C₂₁H₁₉BrF₃N₃OS+H]⁺.

Step b) Preparation of Compound 3

A mixture of 2 (0.15 g, 0.301 mmol) and t-butyl hydroperoxide (0.77 g ofa 70% solution in water, 6.02 mmol) in methanol and concentrated aqueousammonium hydroxide (3 mL) was stirred overnight at room temperaturetreated with 10% aqueous sodium thiosulfate (20 mL) and concentrated toremove most of the methanol. The remaining aqueous mixture was extractedwith methylene chloride. The methylene chloride extracts were combined,washed with brine, dried over magnesium sulfate and concentrated.Purification of the resultant residue by flash chromatography (silica,95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide)afforded 3 (0.073 g, 52%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ7.63 (t, J=1.8 Hz, 1 H), 7.49 (dd, J=6.8, 2.0 Hz, 2H), 7.49-7.37 (m,2H), 7.20-7.13 (m, 3H), 3.96 (m, 4 H), 1.90 (m, 4 H), 1.56 (m, 2H); ESIMS m/z 482 [C₂₁H₂₀BrF₃N₄O+H]⁺.

Step c) Preparation of1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluorometh-oxyphenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine

A mixture of 3 (0.065 g, 0.135 mmol), 2-fluoropyridine-3-boronic acid(0.034 g, 0.243 mmol), bis(triphenylphosphino)palladium(II) chloride(0.0047 g, 0.0068 mmol), triphenylphosphine (0.0035 g, 0.014 mmol) andsodium carbonate (0.043 g, 0.405 mmol) in 3:1 DME/water (2.0 mL) washeated at reflux temperature for 1.5 h, cooled to room temperature anddiluted with ethyl acetate and water. The organic layer was separated,washed with brine, dried over magnesium sulfate and concentrated.Purification of the resultant residue by flash chromatography (silica,97:3:0.25 methylene chloride/methanol/concentrated ammonium hydroxide)afforded 0.041 g of a white foam. This material was freeze dried from2:1 acetonitrile/water to afford the title product as a white solid,0.033 g (49% yield), mp 95-99° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.16 (m, 1H), 8.00 (m, 1 H), 7.62 (d, J=1.4 Hz, 1 H), 7.55-7.37 (m, 6H), 7.23 (d,J=8.1 Hz, 2H), 4.07 (m, 2H), 3.96-3.89 (m, 2H), 1.93-1.82 (m, 4H), 1.55(m, 2H); IR (ATR) 1649, 1433, 1251, 1214, 1155 cm⁻¹; ESI MS m/z 498[C₂₆H₂₃F₄N₅O+H]⁺.

EXAMPLE 38 Preparation of8-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-8-(4-methoxymethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

Step a) Preparation of Compound 2

A mixture of 4-bromophenol (4.00 g, 23.1 mmol) in acetonitrile (100 mL)at 0° C. was treated portionwise with sodium hydride (1.10 g of a 60%dispersion in oil, 27.7 mmol). The mixture was stirred for 5 min, thenwarmed to room temperature and stirred for an additional 15 min.Chloromethyl methyl ether (2.23 g, 27.7 mmol) was added dropwise and themixture stirred for 20 min. The solvents were evaporated and the residuepartitioned between ethyl acetate and water. The layers were separatedand the organic layer washed with brine, dried over sodium sulfate,filtered and concentrated to afford 2 (5.30 g, 106%) as a colorless oil:¹H NMR (500 MHz, CDCl₃) 67 7.38 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz,2H), 5.14 (s, 2H), 3.46 (s, 3H).

Step b) Preparation of Compound 3

A small crystal of iodine was added to a stirred mixture of magnesium(0.197 g, 8.20 mmol) in tetrahydrofuran and then heated to 50° C. Asolution of 2 (1.78 g, 8.20 mmol) in tetrahydrofuran was added dropwiseand the mixture stirred for 45 min. The mixture was cooled to roomtemperature and a solution of 3-bromobenzonitrile (1.00 g, 5.49 mmol) intetrahydrofuran was slowly added. The mixture was then heated at 65° C.for 16 h. The reaction was cooled to room temperature, anhydrousmethanol was added and the mixture stirred for 45 min. The mixture wascooled to 0° C. and sodium borohydride (0.415 g, 10.98 mmol) was addedportionwise. The cooling bath was removed and the mixture stirred for 3hr. Saturated ammonium chloride (10 mL) was added, most of the methanoland THF was removed under reduced pressure. The remaining aqueousresidue was extracted with methylene chloride. The combined organiclayers were dried over sodium sulfate and concentrated. Purification ofthe resultant residue by flash chromatography (silica, 4:1 to 1:1hexanes/ethyl acetate) afforded 3 (0.89 g, 50%) as a colorless oil: ¹HNMR (300 MHz, CDCl₃) δ 7.55 (br s,1 H), 7.39-7.23 (m, 4H), 7.15 (t,J=7.8 Hz, 1 H), 6.98 (d, J=8.7 Hz, 2H, 5.15 (s, 2H), 5.14 (s, 1H), 3.46(s, 3H); ESI MS m/z 305 [(C₁₅H₁₆BrNO₂—NH₂)+H]⁺.

Step c) Preparation of Compound 4

A mixture of 3 (0.89 g, 2.76 mmol) in methylene chloride and saturatedaqueous sodium bicarbonate was cooled with an ice bath, treated withthiophosgene (0.35 g, 3.03 mmol) and stirred vigorously for 40 min. Thephases were separated and the aqueous phase was extracted with methylenechloride. The combined organic phases were washed with brine, dried oversodium sulfate and concentrated to afford 4 (0.80 g, 80%) as a yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.28-7.18 (m, 4H),7.04 (d, J=8.8 Hz, 2H), 5.92 (s, 1H), 5.17 (s, 2H), 3.46 (s, 3H).

Step d) Preparation of Compound 5

To a mixture of potassium t-butoxide (0.27 g, 2.41 mmol) intetrahydrofuran at −78° C. was added dropwise a solution of 4 (0.80 g,0.2.19 mmol) and carbon disulfide (0.25 g, 3.28 mmol) intetrahydrofuran. The reaction was stirred at −78° C. for 0.5 h, thenwarmed to room temperature slowly and stirred for 1.5 h at roomtemperature. After this time, TLC analysis indicated that the reactionwas not complete, so the mixture was cooled to −78° C. and carbondisulfide (0.06 g, 0.83 mmol) was added followed by a solution ofpotassium t-butoxide (0.05 g, 0.44 mmol) in tetrahydrofuran. Thereaction was stirred at −78° C. for 30 min, then warmed to roomtemperature and stirred for 45 min. The reaction was then diluted withethyl acetate and water and brine. The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated, to afford 5 (1.1 g, 115%) as a red semi-solid: ¹H NMR (300MHz, CDCl₃) δ 7.48 (t, J=1.8 Hz, 1 H), 7.43 (d, J=7.8 Hz, 1 H),7.30-7.25 (m, 1 H), 7.20 (d, J=8.8 Hz, 2H), 7.14 (t, J=7.9 Hz, 1 H),6.94 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 3.42 (s, 3H).

Step e) Preparation of Compound 6

A mixture of 5 (1.10 g, 2.18 mmol) and 1,3-diaminopropane (0.484 g, 6.54mmol) in ethanol was heated at 70° C. for 1 h, cooled to roomtemperature and concentrated in vacuo. The resultant residue was dilutedwith ethyl acetate, washed sequentially with water and brine, dried oversodium sulfate and concentrated. Purification of this residue by flashchromatography (silica, 4:1 to 3:1 hexanes/ethyl acetate) afforded 6(0.70 g, 72%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.53 (t,J=1.7 Hz, 1 H), 7.47 (dt, J=7.7, 1.4 Hz, 1 H), 7.30-7.17 (m, 3H),7.06-6.97 (m, 3H), 5.17 (s, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.50 (t, J=5.5Hz, 2H), 3.47 (s, 3H), 1.91 (t, J=5.4 Hz, 2H); ESI MS m/z 446[C₂₀H₂₀BrN₃O₂S+H]⁺.

Step f) Preparation of Compound 7

A mixture of 6 (0.630 g, 1.40 mmol) and t-butyl hydroperoxide (3.6 g ofa 70% solution in water, 28 mmol) in methanol and concentrated aqueousammonium hydroxide (18 mL) was stirred at room temperature for 24 h,treated with 10% aqueous sodium thiosulfate (10 mL) and concentrated toremove most of the methanol. The remaining aqueous mixture was extractedwith methylene chloride. The methylene chloride extracts were combined,washed sequentially with water and brine, dried over sodium sulfate andconcentrated. Purification of this residue by flash chromatography(silica, 95:5:0.25 methylene chloride/methanol/concentrated ammoniumhydroxide) afforded 7 (0.400 g, 67%) as an off-white solid: ¹H NMR (300MHz, CDCl₃) δ 7.66 (t, J=1.8 Hz, 1H), 7.40-7.32 (m, 4 H), 7.16 (t, J=7.9Hz, 1 H), 6.97 (d, J=8.9 Hz, 2H), 5.15 (s, 2H), 3.62-3.55 (m, 4 H), 3.45(s, 3H), 1.86 (t, J=5.5 Hz, 2H); ESI MS m/z 429 [C₂₀H₂₁BrN₄O₂+H]⁺.

Step g) Preparation of8-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-8-(4-methoxy-methoxyphenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

A mixture of 7 (0.370 g, 0.860 mmol), 2-fluoropyridine-3-boronic acid(0.243 g, 1.72 mmol), bis(triphenylphosphino)palladium(II) chloride(0.030 g, 0.043 mmol), triphenylphosphine (0.022 g, 0.086 mmol) andsodium carbonate (0.273 g, 2.58 mmol) in 3:1 DME/water (16 mL) washeated at 80° C. for 1 h, cooled to room temperature and diluted withethyl acetate and water. The organic layer was separated, washed withbrine, dried over sodium sulfate and concentrated. Purification of theresultant residue by flash chromatography (silica, 96:4:0.25 methylenechloride/methanol/concentrated ammonium hydroxide) afforded a paleyellow solid, 0.300 g (78% yield). A 0.030 g sample of this solid wasdissolved in acetonitrile and water and freeze dried to afford the titleproduct as an off-white-solid, 0.023 g, mp 95-105° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.16 (dt, J=5.0, 1.7 Hz, 1 H), 7.88-7.80 (m, 1 H), 7.71-7.67(m, 1 H), 7.53-7.44 (m, 2H), 7.41 (d, J=7.6 Hz, 1 H), 7.37 (d, J=8.8 Hz,2H), 7.27-7.20 (m, 1 H), 6.97 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 3.68-3.54(m, 4H), 3.45 (s, 3H), 1.85 (t, J=5.6 Hz, 2H); ESI MS m/z 446[C₂₅H₂₄FN₅O₂+H]⁺.

EXAMPLE 39 Preparation of8-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

Using essentially the same procedures described in Example 38, stepsa-g, and employing compound 1 as starting material, the title productwas obtained as an off-white solid, mp 125-140° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.16 (m, 1 H), 7.87-7.80 (m, 1 H), 7.72 (d, J=1.4 Hz, 1 H),7.56-7.37 (m, 3H), 7.25-7.21 (m, 1 H), 6.98 (d, J=2.1 Hz, 1 H),6.89-6.77 (m, 2H), 4.22 (s, 4H), 3.62-3.55 (m, 4H), 2.95 (br s, 2H),1.88-1.84 (m, 2H); ESI MS m/z 444 [C₂₅H₂₂FN₅O₂+H]⁺.

EXAMPLE 40 Preparation of8-Benzo[1,3]dioxol-5-yl-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

Using essentially the same procedures described in Example 38, stepsa-g, and employing compound 1 as starting material, the title productwas obtained as an off-white solid, mp 106-119 ° C.; ¹H NMR (300 MHz,CD₃OD) δ 8.17-8.14 (m, 1 H), 8.04-7.98 (m, 1 H), 7.56 (d, J=1.2 Hz, 1H), 7.53-7.36 (m, 4H), 6.87 (dd, J=8.2, 1.8 Hz, 1 H), 6.81 (d, J=1.7 Hz,1 H), 6.75 (d, J=8.2 Hz, 1 H), 5.92 (s, 2H), 3.68 (t, J=5.9 Hz, 2H),3.47 (t, J=5.4 Hz, 2H), 1.88-1.84 (m, 2H); ESI MS m/z 430[C₂₄H₂₀FN₅O₂+H]⁺.

EXAMPLE 41 Preparation of8-(4-Difluoromethoxyphenyl)-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine

A mixture of8-[3-(2-fluoropyridin-3-yl)phenyl]-8-(4-methoxymethoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine(1.10 g, 2.46 mmol) and 3 N hydrochloric acid (60 mL) in methanol wasstirred at room temperature for 16 h, neutralized with aqueous sodiumhydroxide and concentrated in vacuo. The residue obtained was trituratedwith ethanol, the solids removed by filtration and the filtrateconcentrated. Purification of the concentrate by flash chromatography(silica, 90:10 methylene chloride/methanol) afforded a white solid (0.70g, 70%). A 0.040 g sample of this solid was further purified bysemi-preparative liquid chromatography to afford4-{6-amino-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl}-phenolas a white solid (0.0073 g), mp 164-181° C.; ¹H NMR (500 MHz, CD₃OD) δ8.15 (d, J=5.0 Hz, 1 H), 8.03-7.97 (m, 1 H), 7.57 (br s, 1 H), 7.54-7.48(m, 1 H), 7.46-7.41 (m, 2H), 7.40-7.36 (m, 1 H), 7.16 (d, J=8.7 Hz, 2H),6.73 (d, J=8.7 Hz, 2H), 3.69 (t, J=6.0 Hz, 2H), 3.50-3.44 (m, 2H),1.90-1.83 (m, 2H); ESI MS m/z 402 [C₂₃H₂₀FN₅O+H]⁺.

A mixture of4-{6-amino-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl}-phenol(0.285 g, 0.710 mmol) and potassium hydroxide (0.396 g, 7.10 mmol) in2-propanol was stirred for 10 min at room temperature, cooled to −45°C., bubbled with FREON 22 (6.7 g, 77.0 mmol) and sealed. The sealedreaction mixture was warmed to room temperature, gradually warmed to 50°C., stirred for 90 min at 50° C., cooled to room temperature, unsealedand quenched by carefully adding the reaction mixture to water. Theaqueous mixture was diluted with methylene chloride and the layersseparated. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. Purification of this residue by flashchromatography (silica, 95:5:0.25 methylenechloride/methanol/concentrated ammonium hydroxide) afforded an off-whitesolid (0.055 g, 17%). This solid was further purified bysemi-preparative LC to afford the title product as a white solid, (0.033g), mp 104-114° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.16 (dt, J=4.7, 1.3 Hz, 1H), 7.85-7.80 (m, 1 H), 7.69 (d, J=1.4 Hz, 1 H), 7.53-7.45 (m, 4H), 7.40(t, J=7.7 Hz, 1 H), 7.25-7.21 (m, 1 H), 7.05 (d, J=8.7 Hz, 2H), 6.47 (t,J=74.0 Hz, 1 H), 3.63-3.55 (m, 4H), 1.91-1.84 (m, 2H); ESI MS m/z 452[C₂₄H₂₀F₃N₅O+H]⁺.

EXAMPLE 42 Preparation of7-[3-(2-Fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine

Step a) Preparation of Compound 2

A solution of 1 (0.250 g, 0.54 mmol) in ethanol at 0° C. was treatedwith 2-methylpropane-1,2-diamine (0.144 g, 1.62 mmol), stirred at 0° C.for 3 h, then at room temperature for 45 minutes, heated to 40° C. for 2h and concentrated in vacuo. The resultant residue was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith brine, dried over sodium sulfate and concentrated. This residue waspurified by flash chromatography (silica, gradient 100% hexanes to 1:9ethyl acetate/hexanes) to afford 2 as a white solid, ¹H NMR (300 MHz,CDCl₃) δ 7.73 (s, 1 H), 7.56 (t, J=1.8 Hz, 1 H ), 7.49 (dt, J=7.7, 1.3Hz, 1 H), 7.43 (t, J=3.0 Hz, 1 H), 7.40 (t, J=2.2 Hz, 1 H), 7.34-7.21(m, 4H), 3.60 (s, 2H), 1.44 (s, 3H), 1.43 (s, 3H); ESI MS m/z 484[C20H₁₇BrF₃N₃OS+H]⁺.

Step b) Preparation of Compound 3

A mixture of 2 (0.201 g, 0.42 mmol) and t-butyl hydroperoxide (0.75 g ofa 70% solution in water, 8.30 mmol) in methanol and concentrated aqueousammonium hydroxide (5 mL) was stirred overnight at room temperature,treated 10% aqueous sodium thiosulfate (30 mL) and concentrated toremove most of the methanol. The remaining aqueous mixture was extractedwith methylene chloride. The methylene chloride extracts were combined,washed with brine, dried over sodium sulfate and concentrated.Purification of the residue by flash chromatography (silica, 97:2.5:0.5methylene chloride/methanol/concentrated ammonium hydroxide) afforded 3(0.134 g, 68%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.71 (t,J=1.7 Hz, 1 H ), 7.54 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.19-7.13(m, 3H), 3.36 (s, 2H), 1.42 (s, 6H); ESI MS m/z 467 [C₂₀H₁₈BrF₃N₄O+H]⁺.

Step c) Preparation of7-[3-(2-fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine

A mixture of 3 (0.134 g, 0.29 mmol), 2-fluoropyridine-3-boronic acid(0.081 g, 0.57 mmol), bis(triphenylphosphino)palladium(II) chloride(0.010 g, 0.015 mmol), triphenylphosphine (0.008 g, 0.029 mmol) andsodium carbonate (0.092 g, 0.87 mmol) in 3:1 DME/water (8.0 mL) washeated at 80° C. for 5 h, cooled to room temperature and diluted withethyl acetate and water. The organic layer was separated, washed withbrine, dried over sodium sulfate and concentrated. Purification of theresultant residue by flash chromatography (silica, 97:2.5:0.5 methylenechloride/methanol/concentrated ammonium hydroxide) afforded 0.020 g ofan off-white solid. This material was freeze dried from 2:1acetonitrile/water (6 mL) to afford the title product as a white solid,0.0189 g (14% yield), mp 89-97° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.18-8.17(m, 1 H), 7.84-7.78 (m, 2H), 7.62-7.54 (m, 3H), 7.48-7.42 (m, 2H), 7.27(m, 1 H), 7.16 (d, J=8.2 Hz, 2H), 3.39 (d, J=2.2 Hz, 2H), 1.44 (s, 3H),1.42 (s, 3H); ESI MS m/z 484 [C₂₅H₂₁F₄N₅O₂+H]⁺.

EXAMPLE 43 Preparation of8-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

Step a) Preparation of Compound 3

A solution of 1 (2.00 g, 8.44 mmol) in diethyl ether (16 mL) was addeddropwise to a mixture of t-butyl lithium (4.96 mL of a 1.7 M solution inpentane, 8.44 mmol) in diethyl ether (20 mL) at −78° C. and stirred atthis temperature for 25 min. To this was added 3-bromobenzonitrile(0.731 g, 4.02 mmol) in diethyl ether (20 mL) at −78° C., and thereaction mixture was stirred at −78° C. for an additional 1.5 h. Thereaction was then warmed to 0° C. and methanol (60 mL) was added,followed by the portion-wise addition of sodium borohydride (0.319 g,8.43 mmol). The cooling bath was removed and then the mixture wasstirred at room temperature for 2 hr. Saturated aqueous ammoniumchloride (10 mL) was added, most of the methanol and diethyl ether wasremoved under reduced pressure and the aqueous residue obtained wasdiluted with methylene chloride (200 mL) and saturated aqueous sodiumbicarbonate solution (30 mL). The organic layer was separated and washedwith brine, dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography (silica, 9:1 hexanes/ethyl acetate)afforded 3 (0.237 g, 18%) as a colorless syrup: ¹H NMR (300 MHz, CDCl₃)δ 7.54 (t, J=1.6 Hz, 1 H), 7.38 (dt, J=7.8, 1.2 Hz, 1 H), 7.29-7.04 (m,4 H), 6.98 (d, J=8.2 Hz, 1 H), 5.17 (s, 1 H); ESI MS m/z 327[(C₁₄H₁₀BrF₂NO₂—NH₂)+H]⁺.

Step b) Preparation of Compound 4

A mixture of 3 (0.416 g, 1.22 mmol) in methylene chloride and saturatedaqueous sodium bicarbonate (6 mL) was cooled with an ice bath, treatedwith thiophosgene (0.154 g, 1.34 mmol) and stirred vigorously for 45minutes. The organic layer was separated, washed with brine (15 mL),dried over sodium sulfate, filtered and concentrated to afford 4 (0.405g, 87%) as a yellow syrup: ¹H NMR (500 MHz, CDCl₃) δ 7.48 (dt, J=7.7,1.6 Hz, 1 H), 7.43 (t, J=6.3 Hz, 1 H), 7.11-7.04 (m, 2H), 6.99 (t, J=0.6Hz, 1 H), 5.95 (s, 1 H); ESI MS m/z 325 [(C₁₅H₈BrF₂NO₂S—NCS)+H]⁺.

Step c) Preparation of Compound 5

To a mixture of potassium t-butoxide (0.130 g, 1.16 mmol) intetrahydrofuran at −78° C. was added dropwise a solution of 4 (0.405 g,1.05 mmol) and carbon disulfide (0.120 g, 1.58 mmol) in tetrahydrofuran,over a period of 5 min. The reaction was stirred at −78° C. for 0.5 h,then warmed to room temperature slowly and stirred overnight at roomtemperature. The reaction was then concentrated to remove most of thetetrahydrofuran and the residue diluted with ethyl acetate, water andbrine. The organic layer was separated, washed with brine, dried oversodium sulfate, filtered and concentrated. Purification by flashchromatography (silica, 9:1 hexanes/ethyl acetate) afforded 5 (0.323 g,67%) as a red syrup: ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.56 (m, 1 H),7.52-7.51 (m, 1 H), 7.35-7.30 (m, 3H), 7.15 (dd, J=8.5, 1.9 Hz, 1 H),7.08 (d, J=1.5 Hz, 1 H).

Step d) Preparation of Compound 6

A mixture of 5 (0.323 g, 0.702 mmol) and 1,3-diaminopropane (0.156 g,2.11 mmol) in ethanol was heated at 70° C. for 1 h and then cooled toroom temperature. The solvents were evaporated and the residue dilutedwith ethyl acetate, washed with water and brine, dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatography(silica, 4:1 hexanes/ethyl acetate) afforded 6 (0.303 g, 93%) as a whitefoam: ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.48 (m, 2H), 7.25 (d, J=1.7 Hz,2H), 7.08-7.04 (m, 3H), 3.88 (t, J=6.0 Hz, 2H), 3.61 (t, J=1.9 Hz, 2H),1.93-1.89 (m, 2H); ESI MS m/z 466 [C₁₉H₁₄BrF₂N₃O₂S+H]⁺.

Step e) Preparation of Compound 7

A mixture of 6 (0.303 g, 0.65 mmol) and t-butyl hydroperoxide (1.18 g ofa 70% solution in water, 12.9 mmol) in methanol and concentrated aqueousammonium hydroxide (6.0 mL) was stirred overnight at room temperature.After this time, 10% aqueous sodium thiosulfate (40 mL) was added; themixture concentrated to remove most of the methanol and then the aqueousmixture was extracted with methylene chloride. The methylene chlorideextracts were combined and washed with brine, dried over sodium sulfate,filtered and concentrated. Purification by flash chromatography (silica,97:2.5:0.5 methylene chloride/methanol/concentrated ammonium hydroxide)afforded 7 (0.208 g, 71%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.63 (t, J=1.8 Hz, 1 H), 7.36 (dd, J=8.0, 1.9 Hz, 2H), 7.24-7.13 (m,3H), 6.95 (dd, J=7.4, 1.7 Hz, 1 H), 3.58 (t, J=5.8 Hz, 4H), 1.89-1.82(m, 2H); ESI MS m/z 449 [C₁₉H₁₅BrF₂N₄O₂+H]⁺.

Step f) Preparation of8-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine

A mixture of 7 (0.208 g, 0.46 mmol), 2-fluoropyridine-3-boronic acid(0.131 g, 0.93 mmol), bis(triphenylphosphino)palladium(II) chloride(0.016 g, 0.023 mmol), triphenylphosphine (0.012 g, 0.046 mmol) andsodium carbonate (0.146 g, 1.38 mmol) in 3:1 DME/water was heated at 80°C. for 2 h then stirred at room temperature overnight. The mixture wasdiluted with ethyl acetate and water. The organic layer was separatedand washed with brine, dried over sodium sulfate, filtered andconcentrated. Purification by flash chromatography (silica, 97:2.5:0.5methylene chloride/methanol/concentrated ammonium hydroxide) afforded acolorless oil (0.180 g (84%). The oil was further purified bysemi-preparative LC to afford the title product as an off-white solid,0.045 g, mp 95-99° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.16-8.15 (m, 1 H),8.03-7.99 (m, 1 H), 7.56 (d, J=1.5 Hz, 1 H), 7.53-7.52 (m, 1 H), 7.46(t, J=7.8 Hz, 1 H), 7.42-7.37 (m, 2H), 7.23-7.19 (m, 2H), 7.13 (d, J=8.3Hz, 1 H), 3.69 (t, J=5.9 Hz, 2H), 3.49 (t, J=5.8 Hz, 2H), 1.89-1.84 (m,2H); ESI MS m/z 466 [C₂₄H₁₈F₃N₅O₂+H]⁺.

EXAMPLE 44 Preparation of8′-[4-(Difluoromethoxy)phenyl]-8′-[3-(2-fluoropyridin-3-yl)phenyl]-2′,8′-dihydrospiro[cyclopropane-1,3′-imidazo[1,5-a]pyrimidin]-6′-amine

Using essentially the same procedure described in Example 42 andemploying 1,1-di(aminomethyl)propane (2) as reactant, the title productwas obtained as a tan solid, mp 98-108° C.; ¹H NMR (500 MHz, CDCl₃) δ8.16 (m, 1 H), 7.83 (m, 1 H), 7.71 (m, 1 H), 7.47 (m, 4H), 7.40 (t,J=7.7 Hz, 1 H), 7.24 (m, 1 H), 7.05 (d, J=6.9 Hz, 2H), 6.49 (t, J=74 Hz,1 H), 3.20-3.45 (m, 4H), 0.57-0.67 (m, 4H); ESI MS m/z 478[C₂₆H₂₂F₃N₅O+H]⁺.

EXAMPLE 45 Preparation of(8R)-8-(4-Difluoromethoxy-phenyl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine[A] and(8S)-8-(4-Difluoromethoxy-phenyl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine[B]

A racemic mixture of8-(4-difluoromethoxy-phenyl)-8-[3-(2-fluoro-pyridin-3-yl)-phenyl]-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylaminewas separated into it's enantiomers using a chiralpak AD 5×50 cm column(90:10:0.1 heptane/ethanol/diethylamine to afford the title R-isomer (A)as a white solid, mp 97-109° C.;

[α]_(D) ²⁵+7.80° (0.48% in MeOH); ¹H NMR (500 MHz, CDCl₃) δ 8.16 (dt,J=4.8, 1.5 Hz, 1 H), 7.86-7.81 (m, 1 H), 7.69 (d, J=1.5 Hz, 1 H),7.52-7.46 (m, 4H), 7.40 (t, J=7.7 Hz, 1 H), 7.26-7.22 (m, 1 H), 7.05 (d,J=8.7 Hz, 2H), 6.48 (t, J=74.0 Hz, 1 H), 3.62 (t, J=6.0 Hz, 2H),3.60-3.56 (m, 2H), 1.87 (quintet, J=5.8 Hz, 2H); ESI MS m/z 452[C₂₄H₂₀F₃N₅O+H]⁺ and the title S-isomer (B) as a white solid, mp 97-110°C.;[α]_(D) ²⁵−3.2° (0.47% in MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.16 (m, 1H), 7.87-7.80 (m, 1 H), 7.69 (br s, 1 H), 7.51-7.38 (m, 5H), 7.26-7.22(m, 1 H), 7.05 (d, J=8.7 Hz, 2H), 6.48 (t, J=74.0 Hz, 1 H), 3.65-3.57(m, 4H), 1.89-1.85 (m, 2H); ESI MS m/z 452 [C₂₄H₂₀F₃N₅O+H]⁺.

EXAMPLE 46 Preparation of8-[4-(Difluoromethoxy)phenyl]-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,8-dihydrospiro[imidazo[1,5-a]pyrimidine-3,3′-oxetan]-6-amine

Step a) Preparation of Compound 2

A mixture of 1 (1.0 g, 5.22 mmol) and potassium hydroxide (0.345 g of85%, 5.22 mmol) in ethanol (2 mL) was heated at reflux for 3 h. Thereaction was cooled to room temperature, diluted with ethyl acetate (10mL) and the solids that formed removed by filtration. The filtrate wasconcentrated to afford 2 (0.65 g, 80%) as a colorless liquid: ¹H NMR(300 MHz, CDCl₃) δ 4.47 (s, 4 H), 3.95 (s, 4 H).

Step b) Preparation of Compound 3

A mixture of 2 (0.63 g, 4.06 mmol) and sodium azide (0.66 g, 10.2 mmol)in DMSO was heated at 65° C. overnight. The reaction was cooled to roomtemperature, diluted with water and extracted into methylene chloride.The combined methylene chloride extracts were washed with water, driedover sodium sulfate, filtered and concentrated at room temperature to avolume of 2 mL and diluted with THF. This solution was then treated withtriphenylphospine (2.56 g, 9.75 mmol)) in THF and stirred at roomtemperature for 10 min, treated with water (0.29 g, 16.2 mmol) andstirred overnight at room temperature. The mixture was thenconcentrated, diluted with methylene chloride and extracted with 10%aqueous HCl. The combined aqueous extracts were washed with methylenechloride and concentrated to afford 3 (0.51 g, 66%) as a white solid: ¹HNMR (500 MHz, D₂O) δ 4.49 (s, 4H), 3.42 (s, 4H).

Step c) Preparation of Compound 5

A mixture of 4 (0.50 g, 1.12 mmol), 3 (0.50 g, 2.64 mmol) andtriethylamine (0.57 g, 5.60 mmol) in ethanol was heated at 70° C. for 3h, cooled to room temperature, concentrated and partitioned betweenethyl acetate and water. The organic layer was separated, washed withbrine, dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography (silica, 1:4 ethyl acetate/hexanes)afforded 5 (0.389 g, 70%) as a white foam: ¹H NMR (500 MHz, CDCl₃) δ7.61 (s, 1 H), 7.49 (dt, J=7.5, 1.5 Hz, 1 H), 7.47-7.44 (m, 1 H),7.33-7.19 (m, 4 H), 7.11 (d, J=8.8 Hz, 2H), 6.52 (t, J=73.4 Hz, 1 H),4.52-4.47 (m, 4H), 4.14-4.06 (m, 2H), 3.87-3.77 (m, 2H); ESI MS m/z 494[C₂₁H₁₈BrF₂N₃O₂S+H]⁺.

Step c) Preparation of Compound 6

A mixture of 5 (0.389 g, 0.79 mmol) and t-butyl hydroperoxide (1.42 g ofa 70% solution in water, 15.8 mmol) in methanol and concentrated aqueousammonium hydroxide (5.0 mL) was stirred at room temperature for 7 h,treated with 10% aqueous sodium thiosulfate (30 mL)and concentrated toremove most of the methanol. The resultant aqueous mixture was extractedwith methylene chloride. The methylene chloride extracts were combinedand washed with brine, dried over sodium sulfate, filtered andconcentrated. Purification of this residue by flash chromatography(silica, 95:5:0.25 methylene chloride/methanol/concentrated ammoniumhydroxide) afforded 6 (0.179 g, 47%) as a white foam: ¹H NMR (300 MHz,CDCl₃) δ 7.56 (t, J=1.7 Hz, 1 H), 7.40-7.37 (m, 1H), 7.38 (d, J=8.8 Hz,2H), 7.29-7.26 (m, 1 H), 7.15 (t, J=7.9 Hz, 1 H), 7.04 (d, J=8.7 Hz,2H), 6.48 (t, J=73.9 Hz, 1 H), 4.57-4.53 (m, 2H), 4.46-4.42 (m, 2H),3.79 (s, 4H); ESI MS m/z 477 [C₂₁H₁₉BrF₂N₄O₂+H]⁺.

Step d) Preparation of of8-[4-(difluoromethoxy)phenyl]-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,8-dihydrospiro[imidazo[1,5-a]pyrimidine-3,3′-oxetan]-6-amine

A mixture of 6 (0.10 g, 0.21 mmol), 2-fluoropyridine-3-boronic acid(0.035 g, 0.250 mmol), bis(triphenylphosphino)palladium(II) chloride(0.0073 g, 0.11 mmol), triphenylphosphine (0.0055 g, 0.021 mmol) andsodium carbonate (0.066 g, 0.63 mmol) in 3:1 DME/water was heated atreflux temperature for 2 h, cooled to room temperature and diluted withethyl acetate and water. The organic layer was separated and washed withbrine, dried over sodium sulfate, filtered and concentrated.Purification of this residue by flash chromatography (silica, 97:2.5:0.5methylene chloride/methanol/concentrated ammonium hydroxide) afforded ayellow foam (0.089 g, 85%). This foam was further purified bysemi-preparative LC to afford the title product as a white solid; mp96-107° C.; ¹H NMR (500 MHz, CD₃OD) □8.17-8.16 (m, 1 H), 8.02-7.98 (m, 1H), 7.52-7.51 (m, 2H), 7.45 (t, J=7.9 Hz, 1 H), 7.40-7.34 (m, 4H), 7.09(d, J=8.8 Hz, 2H), 6.01 (t, J=74.1 Hz, 1 H) 4.50-4.47 (m, 4H), 3.97-3.89(m, 2H), 3.76-3.69 (m, 2H); ESI MS m/z 496 [C₂₆H₂₂F₃N₅O₂+H]⁺;

EXAMPLE 47 Preparation of8′-[4-(difluoromethoxy)phenyl]-8′-[3-(2-fluoropyridin-3-yl)phenyl]-2′,8′-dihydrospiro[cyclobutane-1,3′-imidazo[1,5-a]pyrimidin]-6′-amine

Using essentially the same procedure described in Example 44 andemploying 1,1-di(aminomethylcyclobutane as starting reactant, the titleproduct was obtained as a white solid, mp 220-226° C.; ¹H NMR (500 MHz,CD₃OD) □8.16-8.15 (m, 1 H), 8.01-7.97 (m, 1 H), 7.54-7.51 (m, 2H), 7.44(t, J=7.8 Hz, 1 H), 7.40-7.37 (m, 4H), 7.08 (d, J=8.8 Hz, 2H), 6.80 (t,J=74.1 Hz, 1 H), 3.65-3.58 (m, 2H), 3.46-3.39 (m, 2H), 2.09-2.01 (m,2H), 1.92-1.87 (m, 4H); ESI MS m/z 492 [C₂₇H₂₄F₃N₅O+H]⁺.

EXAMPLE 48 Evaluation of the Enzyme Activity of Test Compounds and theInhibition of hBACE1, MuBACE1 and hBACE2 by Test Compounds

Assay Conditions

10 nM human BACE1 (or 10 nM Murine BACE1, 1.5 nM human BACE2) 25 μMsubstrate (WABC-6, MW 1549.6, from AnaSpec); final buffer conditions: 50mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS; temperature: roomtemperature; reagent information: Na-Acetate: Aldrich, Cat.# 24,124-5CHAPS: Research Organics, Cat. # 1304C 1×PBS: Mediatech (Cellgro), Cat#21-031-CV; peptide substrate AbzSEVNLDAEFRDpa: AnaSpec, Peptide Name:WABC-6; determination of stock substrate (AbzSEVNLDAEFRDpa)concentration: a 25 mM stock solution in dimethyl sulfoxide (DMSO) isprepared using the peptide weight and MW and diluted to 25 μM. Theconcentration is determined by absorbance at 354 nm using an extinctioncoefficient ε of 18172 M⁻¹cm⁻¹, The substrate stock is stored in smallaliquots at −80° C. [Substrate Stock]=ABS^(354 nm)*10⁶/18172 (in mM)

Determination of Stock Enzyme Concentration

The stock concentration of each enzyme by ABS at 280 nm using □ of 64150M⁻¹cm⁻¹ for hBACE1 and MuBACE1, 62870 M⁻¹cm⁻¹ for hBACE2 in 6 MGuanidinium Hydrochloride (from Research Organics, Cat. # 5134G-2), pH6. (The extinction coefficient ε^(280 nm) for each enzyme was calculatedbased on known amino acid composition and published extinctioncoefficients for Trp (5.69 M⁻¹ cm⁻¹) and Tyr (1.28 M⁻¹ cm⁻¹) residues(Anal. Biochem. 182, 319-326).

Dilution and mixing steps: total reaction volume: 100 μL

-   1. 2× inhibitor dilutions in buffer A (66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   2. 4× enzyme dilution in buffer A (66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   3. 100 μM substrate dilution in 1× PBS is prepared,-   4. 50 μL 2× Inhibitor and 25 μL 100 μM substrate are added to each    well of 96-well plate (from DYNEX Technologies, VWR #: 11311-046),    the immediately 25 μL 4× enzyme are added to the inhibitor and    substrate mixer, the fluorescence readings are initiated.

Fluorescence Readings

Readings at λ_(ex) 320 nm and λ_(em) 420 nm are taken every 40-sec for30 min at room temperature to determine the linear slope for substratecleavage rate (v_(i)).

Calculation of % Inhibition: % Inhibition=100*(1−v_(i)/v₀)

-   (v_(i)=substrate cleavage rate in the presence of inhibitor,-   v₀=substrate cleavage rate in the absence of inhibitor)-   IC₅₀ Determination: % Inhibition=[(B*IC₅₀ ^(n))+(100*I₀ ^(n))]/(IC₅₀    ^(n)+I₀ ^(n)),

Fluorescent Kinetic Assay for Human Recombinant BACE 2

This assay is used to provide kinetic and selectivity parameters for theanalyses of the tested compounds.

Materials and methods: final assay conditions:10 nM human BACE1 (or 10nM Murine BACE1, 1.5 nM human BACE2) 25 μM Substrate (WABC-6, MW 1549.6,from AnaSpec). Final buffer conditions: 50 mM Na-Acetate, pH 4.5, 0.05%CHAPS, 25% PBS. Temperature: room temperature. Reagent Information:Na-Acetate: Aldrich, Cat.# 24,124-5 CHAPS: Research Organics, Cat. #1304C 1× PBS: Mediatech (Cellgro), Cat# 21-031-CV Peptide SubstrateAbzSEVNLDAEFRDpa: AnaSpec, Peptide Name: WABC-6

Determination of Stock Substrate (AbzSEVNLDAEFRDpa) Concentration

A 25 mM stock solution in DMSO is prepared using the peptide weight andMW, and diluted to 25 μM. The concentration is determined by absorbanceat 354 nm using an extinction coefficient ε of 18172 M⁻¹cm⁻¹. Thesubstrate stock is stored in small aliquots at −80° C. [SubstrateStock]=ABS^(354 nm)*10⁶/18172 (in mM)

Determination of Stock Enzyme Concentration

The stock concentration of each enzyme is determined by ABS at 280 nmusing ε of 64150 M⁻¹cm⁻¹ for hBACE1 and MuBACE1, 62870 M⁻¹cm⁻¹ forhBACE2 in 6 M guanidinium hydrochloride (from Research Organics, Cat. #5134G-2), pH 6. (The extinction coefficient ε^(280 nm) for each enzymeis calculated based on known amino acid composition and publishedextinction coefficients for Trp (5.69 M⁻¹ cm⁻¹) and Tyr (1.28 M⁻¹ cm⁻¹)residues (Anal. Biochem. 182, 319-326).)

Dilution and Mixing Steps: Total Reaction Volume.: 100 μL

-   1. 2× inhibitor dilutions in buffer A (66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   2. 4× enzyme dilution in buffer A (66.7 mM Na-Acetate, pH 4.5,    0.0667% CHAPS) are prepared,-   3. 100 μM substrate dilution in 1× PBS, 50 μL 2× Inhibitor and 25 μL    100 μM substrate are added to each well of 96-well plate (from DYNEX    Technologies, VWR #: 11311-046), then immediately 25 μL 4× enzyme is    added to the inhibitor and substrate mixer and the fluorescence    readings are initiated.

Fluorescence Readings

Readings at λ_(ex) 320 nm, λ_(em) 420 nm are taken every 40-sec for 30min at room temperature and to determine the linear slope for substratecleavage rate (v_(i)).

Analysis of calculation of % inhibition: % Inhibition=100*(1−v_(i)/v₀)

-   v_(i)=substrate cleavage rate in the presence of inhibitor,-   v₀=substrate cleavage rate in the absence of inhibitor)-   IC₅₀ Determination:-   % Inhibition=((B*IC₅₀ ^(n))+(100*I₀ ^(n)))/(IC₅₀ ^(n)+I₀ ^(n)),

The data obtained are shown in Table II below. Unless otherwise noted,the IC₅₀ value represents the value obtained at 100% inhibition.

TABLE II Ex. IC₅₀ (μM) No. BACE1. BACE2.  5 0.23 25 (50% inhibition) 130.15 25 (25% inhibition) 14 0.14 25 (65% inhibition) 15 0.10 25 (44%inhibition) 16 0.11 25 (49% inhibition) 17 0.06 11.39 18 0.06 25 (62%inhibition) 19 0.08 3.22 20 0.04 0.54 21 0.09 6.57 22 0.12 25 (60%inhibition) 23 0.12 25 (42% inhibition) 24 0.06 8.18 25 0.083 9.867 260.04 1.66 27 0.10 4.44 28 0.06 4.68 30A 0.37 25 (35% inhibition) 30B0.02 3.79 31A 0.03 10.37 31B 0.79 25 (28% inhibition) 32A 0.029 0.27232B 19% at 5 uM 34% at 25 μM 33A 0.05 4.00 33B 43% at 5 μM 25% at 25 μM34 0.979 25% at 25 μM 35 0.072 12.252 36 0.071 7.319 37 0.152 10.803 380.093 47% at 15.5 μM   39 0.194 10.532 40 0.160 4.374 41 0.018 1.234 420.15 52% at 25 μM 41 0.018 1.234 42 0.15 52% at 25 μM 43 0.74 53% at 25μM 44 0.02 2.26 45A 0.01 0.70 45B 49% at 2.5 uM   60% at 25 μM 46 0.010.55 47 0.01 1.15

Results and Discussion

As can be seen from the data shown on Table II hereinabove, thecompounds of the invention are potent and selective inhibitors of BACE1.

1. A compound of formula I

wherein X is N, NO or CR₁₉; Y is N, NO or CR₁₁; Z is N, NO or CR₂₀ withthe proviso that no more than two of X, Y or Z may be N or NO; R₁ and R₂are each independently H, CN or an optionally substituted C₁-C₄alkylgroup; R₃ and R₄ are each independently H, or an optionally substitutedC₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a 3- to7-membered ring optionally containing one or two heteroatoms selectedfrom O, N or S or R₃ may be taken together with the atom to which it isattached and an adjacent carbon atom to form a double bond; R₅ and R₆are each independently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup each optionally substituted or when attached to adjacent carbonatoms R₅ and R₆ may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one or two heteroatoms selected from O, N or S;R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, halogen,NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group each optionally substituted; mis 0 or 1; n is 0, 2 or 3;

is a single bond or a double bond with the proviso that when m is 0 then

must be a single bond; R₁₂, R₁₃ and R₁₆ are each independently H or aC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl or aryl group each optionally substituted; and R₁₄, R₁₅, R₁₇and R₁₈ are each independently H or C₁-C₄alkyl; or a tautomer thereof, astereoisomer thereof or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1 wherein R₁ and R₂ are H.
 3. Thecompound according to claim 1 wherein m and n are
 1. 4. The compoundaccording to claim 1 having the structure Ia


5. The compound according to claim 4 having the structure Ib


6. The compound according to claim 5 wherein R₁ and R₂ are H.
 7. Thecompound according to claim 6 wherein X is N.
 8. The compound accordingto claim 7 wherein n is 0 or
 2. 9. The compound according to claim 1selected from the group consisting of:7-[(3-(Pyrimidin-5-yl)phenyl]-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine;7-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluoromethoxy-phenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine;1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine;and7-[3-(2-Fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;a tautomer thereof; or a pharmaceutically acceptable salt thereof
 10. Amethod for the treatment, prevention or amelioration of a disease ordisorder characterized by elevated β-amyloid deposits or β-amyloidlevels in a patient which comprises providing said patient with atherapeutically effective amount of a compound of formula I

wherein X is N, NO or CR₁₉; Y is N, NO or CR₁₁; Z is N, NO or CR₂₀ withthe proviso that no more than two of X, Y or Z may be N or NO; R₁ and R₂are each independently H, CN or an optionally substituted C₁-C₄ alkylgroup; R₃ and R₄ are each independently H, or an optionally substitutedC₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a 3- to7-membered ring optionally containing one or two heteroatoms selectedfrom O, N or S or R₃ may be taken together with the atom to which it isattached and an adjacent carbon atom to form a double bond; R₅ and R₆are each independently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup each optionally substituted or when attached to adjacent carbonatoms R₅ and R₆ may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one or two heteroatoms selected from O, N or S;R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, halogen,NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group each optionally substituted; mis 0 or 1; n is 0, 2 or 3;

is a single bond or a double bond with the proviso that when m is 0 then

must be a single bonds R₁₂, R₁₃ and R₁₆ are each independently H or aC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl or aryl group each optionally substituted; and R₁₄, R₁₅, R₁₇and R₁₈ are each independently H or C₁-C₄ alkyl; or a tautomer thereof,a stereoisomer thereof or a pharmaceutically acceptable salt thereof.11. The method according to claim 10 having a formula I compound whereinthe structure is Ia


12. The method according to claim 11 having a formula I compound whereinthe structure is Ib


13. The method according to claim 12 wherein said disease or disorder isselected from the group consisting of Alzheimer's disease; mildcognitive impairment; Down's syndrome; hereditary cerebral hemorrhagewith amyloidosis of the Dutch type; cerebral amyloid angiopathy; anddegenerative dementia.
 14. The method according to claim 13 wherein saiddisease is Alzheimer's disease.
 15. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound of formula I

wherein X is N, NO or CR₁₉; Y is N, NO or CR₁₁; Z is N, NO or CR₂₀ withthe proviso that no more than two of X, Y or Z may be N or NO; R₁ and R₂are each independently H, CN or an optionally substituted C₁-C₄ alkylgroup; R₃ and R₄ are each independently H, or an optionally substitutedC₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a 3- to7-membered ring optionally containing one or two heteroatoms selectedfrom O, N or S or R₃ may be taken together with the atom to which it isattached and an adjacent carbon atom to form a double bond; R₅ and R₆are each independently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup each optionally substituted or when attached to adjacent carbonatoms R₅ and R₆ may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one or two heteroatoms selected from O, N or S;R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, halogen,NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group each optionally substituted; mis 0 or 1; n is 0, 2 or 3;

is a single bond or a double bond with the proviso that when m is 0 then

must be a single bond, R₁₂, R₁₃ and R₁₆ are each independently H or aC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl or aryl group each optionally substituted; and R₁₄, R₁₅, R₁₇and R₁₈ are each independently H or C₁-C₄alkyl; or a tautomer thereof, astereoisomer thereof or a pharmaceutically acceptable salt thereof. 16.The composition according to claim 15 having a formula I compoundwherein the structure is Ia


17. The composition according to claim 16 having a formula I compoundwherein the structure is Ib


18. The composition according to claim 17 wherein R₁ and R₂ are H and Yis CR₁₁.
 19. The composition according to claim 15 having a formula Icompound selected from the group consisting of:7-[(3-(Pyrimidin-5-yl)phenyl]-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine;7-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluoromethoxy-phenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine;1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine;and7-[3-(2-Fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;a tautomer thereof; or a pharmaceutically acceptable salt thereof.
 20. Aprocess for the preparation of a compound of formula I

wherein X is N, NO or CR₁₉; Y is N, NO or CR₁₁; Z is N, NO or CR₂₀ withthe proviso that no more than two of X, Y or Z may be N or NO; R₁ and R₂are each independently H, CN or an optionally substituted C₁-C₄ alkylgroup; R₃ and R₄ are each independently H, or an optionally substitutedC₁-C₄ alkyl group or R₃ and R₄ may be taken together to form a 3- to7-membered ring optionally containing one or two heteroatoms selectedfrom O, N or S or R₃ may be taken together with the atom to which it isattached and an adjacent carbon atom to form a double bond; R₅ and R₆are each independently H, halogen, NO₂, CN, OR₁₃, NR₁₄R₁₅ or a C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup each optionally substituted or when attached to adjacent carbonatoms R₅ and R₆ may be taken together with the atoms to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one or two heteroatoms selected from O, N or S;R₇, R₈, R₉, R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, halogen,NO₂, CN, OR₁₆, NR₁₇R₁₈ or a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group each optionally substituted; mis 0 or 1; n is 0, 2 or 3;

is a single bond or a double bond with the proviso that when m is 0 then

must be a single bond; R₁₂, R₁₃ and R₁₆ are each independently H or aC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl or aryl group each optionally substituted; and R₁₄, R₁₅, R₁₇and R₁₈ are each independently H or C₁-C₄ alkyl; which process comprisesreacting a compound of formula II

wherein Hal is Cl or Br.

wherein W is B(OH)₂, Sn(n Bu)₃ or Sn(CH₃)₃ and X, Y, Z, R₈, R₉ and m areas described for formula I hereinabove in the presence of a palladiumcatalyst optionally in the presence of a solvent.